2-phenylpyrimidine-4-carboxamides as ahr inhibitors

ABSTRACT

The present invention covers 2-phenylpyrimidine-4-carboxamide compounds of general formula (I): (I) 5 in which X, Y, Z, R1, R2, R4, R5 and R6 are as defined herein, methods of preparing said compounds, intermediate compounds useful for preparing said compounds, pharmaceutical compositions and combinations comprising said compounds and the use of said compounds for manufacturing pharmaceutical compositions for the treatment or prophylaxis of diseases, in particular of cancer or conditions with 10 dysregulated immune responses or other disorders associated with aberrant AHR signaling, as a sole agent or in combination with other active ingredients.

The present invention covers 2-phenylpyrimidine-4-carboxamide compoundsof general formula (I) as described and defined herein, methods ofpreparing said compounds, intermediate compounds useful for preparingsaid compounds, pharmaceutical compositions and combinations comprisingsaid compounds, and the use of said compounds for manufacturingpharmaceutical compositions for the treatment or prophylaxis ofdiseases, in particular cancer or conditions with dysregulated immuneresponses, as a sole agent or in combination with other activeingredients.

BACKGROUND

The AHR (Aryl Hydrocarbon Receptor) is a ligand-activated transcriptionfactor, belonging to the basic helix-loop-helix/Per-Arnt-Sim (bHLH/PAS)family, and is located in the cytosol. Upon ligand binding, the AHRtranslocates to the nucleus where it heterodimerises with ARNT (AHRNuclear Translocator) upon which it interacts with DREs (Dioxin ResponseElements) of AHR-responsive genes to regulate their transcription. TheAHR is best known for binding to environmental toxins and inducing themetabolic machinery, such as cytochrome P 450 enzymes (eg. CYP1A1,CYP1A2 and CYP1B1), required for their elimination (Reyes et al.,Science, 1992, 256(5060):1193-5). Activation of AHR by xenobiotics hasdemonstrated its role in numerous cellular processes such asembryogenesis, tumourigenesis and inflammation. AHR is expressed in manycells of the immune system, including dendritic cells (DCs),macrophages, T cells and NK cells, and plays an important role inimmunoregulation (Nguyen et al., Front Immunol, 2014, 5:551). Theclassic exogenous AHR ligands TCDD and 3-methylcholanthrene, forexample, are known to induce profound immunosuppression, promotecarcinogenesis and induce tumour growth (Gramatzki et al., Oncogene,2009, 28(28):2593-605; Bui et al., Oncogene, 2009, 28(41):3642-51; Esseret al., Trends Immunol, 2009, 30:447-454). In the context ofimmunosuppression, AHR activation promotes regulatory T cell generation,inhibits Th1 and Th17 differentiation, directly and indirectly, anddecreases the activation and maturation of DCs (Wang et al., Clin ExpImmunol, 2014, 177(2):521-30; Mezrich et al., J Immunol, 2010, 185(6):3190-8; Wei et al., Lab Invest, 2014, 94(5):528-35; Nguyen et al., PNAS,2010, 107(46):19961-6). AHR activation modulates the innate immuneresponse and constitutive AHR expression has been shown to negativelyregulate the type-I interferon response to viral infection (Yamada etal., Nat Immunol, 2016). Additionally, mice with a constitutively activeAHR spontaneously develop tumours (Andersson et al., PNAS, 2002,99(15):9990-5).

In addition to xenobiotics, the AHR can also bind metabolic products oftryptophan degradation. Tryptophan metabolites, such as kynurenine andkynurenic acid, are endogenous AHR ligands that activate the AHR underphysiological conditions (DiNatale et al., Toxicol Sci, 2010,115(1):89-97; Mezrich et al., J Immunol, 2010, 185(6):3190-8; Opitz etal., Nature, 2011, 478(7368):197-203). Other endogenous ligands areknown to bind the AHR although their physiological roles are currentlyunknown (Nguyen & Bradfield, Chem Res Toxicol, 2008, 21(1):102-116).

The immunosuppressive properties of kynurenine and tryptophandegradation are well described and are implicated in cancer-associatedimmunosuppression. The enzymes indoleamine-2,3-dioxygenases 1 and 2(IDO1/IDO2) as well as tryptophan-2,3-dioxygenase 2 (TDO2) areresponsible for catalysing the first and rate-limiting step oftryptophan metabolism. IDO1/2-mediated degradation of tryptophan intumours and tumour-draining lymph nodes reduces anti-tumour immuneresponses and inhibition of IDO can suppress tumour formation in animalmodels (Uyttenhove et al., Nat Med, 2003, 9(10):1269-74; Liu et al.,Blood, 2005, 115(17): 3520-30; Muller et al., Nat Med, 11(3):312-9;Metz, Cancer Res, 2007, 67(15):7082-7).

TDO2 is also strongly expressed in cancer and can lead to the productionof immunosuppressive kynurenine. In glioma, activation of the AHR bykynurenine, downstream of TDO-mediated tryptophan degradation, enhancestumour growth as a consequence of inhibiting anti-tumour immuneresponses as well as directly promoting tumour cell survival andmotility (Opitz et al., Nature, 2011, 478(7368):197-203). AHR ligandsgenerated by tumour cells therefore act in both an autocrine andparacrine fashion on tumour cells and lymphocytes, respectively, topromote tumour growth.

The present invention covers 2-phenylpyrimidine-4-carboxamide compoundsof general formula (I) which inhibit the AHR.

STATE OF THE ART

WO 2010/059401 relates to compounds and compositions for expanding thenumber of CD34+ cells for transplantation. In particular, WO 2010/059401relates inter alia to heterocyclic compounds capable of down-regulatingthe activity and/or expression of AHR.

WO 2012/015914 relates to compositions and methods for modulating AHRactivity. In particular, WO 2012/015914 relates inter alia toheterocyclic compounds that modulate AHR activity for use in therapeuticcompositions.

WO 2007/058392 relates to novel heterocyclic compounds and apharmaceutical use thereof. In particular, WO 2007/058392 relates interalia to heterocyclic compounds having an hepatitis C virus cellinfection inhibitory activity.

U.S. Pat. No. 5,418,233 relates to heterobiaryl derivatives inhibitingcell-cell aggregation and cell-matrix interactions. In particular, U.S.Pat. No. 5,418,233 relates to heterobiaryl derivatives which arehistamine receptor antagonists.

WO 2006/053903 relates to low-molecular inhibitors of cytohesin-familyguanine nucleotide exchange factors. In particular, WO 2006/053903relates inter alia to pyrimidine compounds.

WO 2008/058995 relates to cytohesin inhibitors. In particular, WO2008/058995 relates inter alia to pyrimidine compounds.

WO 2008/009963 relates to pyrimidine derivatives. In particular, WO2008/009963 relates to parathyroid hormone and parathyroid hormonerelated protein receptor ligands.

However, the state of the art does not describe the2-phenylpyrimidine-4-carboxamide compounds of general formula (I) of thepresent invention as described and defined herein.

It has now been found, and this constitutes the basis of the presentinvention, that the compounds of the present invention have surprisingand advantageous properties.

In particular, the compounds of the present invention have surprisinglybeen found to effectively inhibit AHR for which data are given inbiological experimental section and may therefore be used for thetreatment or prophylaxis of cancer or other conditions where exogenousand endogenous AHR ligands induce dysregulated immune responses,uncontrolled cell growth, proliferation and/or survival of tumour cells,immunosuppression in the context of cancer, inappropriate cellularimmune responses, or inappropriate cellular inflammatory responses ordiseases which are accompanied with uncontrolled cell growth,proliferation and/or survival of tumour cells, immunosuppression in thecontext of cancer inappropriate cellular immune responses, orinappropriate cellular inflammatory responses, particularly in which theuncontrolled cell growth, proliferation and/or survival of tumour cells,immunosuppression in the context of cancer, inappropriate cellularimmune responses, or inappropriate cellular inflammatory responses ismediated by AHR, such as, for example, liquid and solid tumours, and/ormetastases thereof, e.g. head and neck tumours including brain tumoursand brain metastases, tumours of the thorax including non-small cell andsmall cell lung tumours, gastrointestinal tumours including colon,colorectal and pancreatic tumours, liver tumours, endocrine tumours,mammary and other gynecological tumours, urological tumours includingrenal, bladder and prostate tumours, skin tumours, and sarcomas, and/ormetastases thereof.

DESCRIPTION OF THE INVENTION

In accordance with a first aspect, the present invention coverscompounds of general formula (I):

in which

-   X represents CH or N;-   Y represents CR³ or N;-   Z represents CH or N, wherein    -   if X represents N, Y represents CR³ and Z represents CH, and    -   if X represents CH, Z represents CH and Y represents CR³ or N,        and    -   if Z represents N, Y represents N and X represents CH;-   R¹ represents C₂-C₈-hydroxyalkyl, wherein said C₂-C₈-hydroxyalkyl    groups are optionally substituted once with R⁷ and optionally one to    three times with halogen, or    -   C₃-C₆-cycloalkyl substituted once with hydroxy or        C₁-C₃-hydroxyalkyl and optionally one to three times with        halogen, or    -   (C₃-C₆-cycloalkyl substituted once with hydroxy)-C1-C₄-alkyl, or    -   5- to 6-membered heterocycloalkyl optionally substituted once        with hydroxy or C₁-C₃-hydroxyalkyl and optionally one to three        times with halogen, or    -   (5- to 6-membered heterocycloalkyl optionally substituted once        with hydroxy)-C₁-C₄-alkyl;-   R² represents hydrogen, chloro, methyl, fluoromethyl,    difluoromethyl, trifluoromethyl, methoxy, difluoromethoxy,    trifluoromethoxy or —NR⁸R⁹;-   R³ represents hydrogen, halogen or methyl;-   R⁴ represents hydrogen, methyl, fluoromethyl, difluoromethyl,    trifluoromethyl, methoxy, halogen or cyano;-   R⁵ represents hydrogen, halogen, methyl, fluoromethyl,    difluoromethyl, trifluoromethyl, methoxy, difluoromethoxy or    trifluoromethoxy;-   R⁶ represents hydrogen or halogen;-   R⁷ represents C₁-C₄-alkoxy, —CO₂—R¹⁰, —CO—NR⁸R⁹, cyano, —NR⁸R⁹,    C₃-C₆-cycloalkyl, 5- to 6-membered heterocycloalkyl, phenyl or    monocyclic heteroaryl;-   R⁸ and R⁹ are the same or different and represent, independently    from each other, hydrogen or C₁-C₃-alkyl, or    -   together with the nitrogen atom to which they are attached form        a 4- to 6-membered nitrogen containing heterocyclic ring, said        ring optionally containing one additional heteroatom selected        from O, S, NH, NR^(a) in which R^(a) represents a C₁-C₄-alkyl        group;-   R¹⁰ represents hydrogen or C₁-C₄-alkyl;    their polymorphs, enantiomeres, diastereomeres, racemates,    tautomeres, N-oxides, hydrates and solvates, as well as their    physiological acceptable salts and solvates of these salts, as well    as mixtures of the same.

Further, it covers their use in combination with other anti cancermedications such as immunotherapeutics, targeted anti cancer agents orchemotherapy.

Definitions

The term “substituted” means that one or more hydrogen atoms on thedesignated atom or group are replaced with a selection from theindicated group, provided that the designated atom's normal valencyunder the existing circumstances is not exceeded. Combinations ofsubstituents and/or variables are permissible.

The term “optionally substituted” means that the number of substituentscan be equal to or different from zero. Unless otherwise indicated, itis possible that optionally substituted groups are substituted with asmany optional substituents as can be accommodated by replacing ahydrogen atom with a non-hydrogen substituent on any available carbonatom. Commonly, it is possible for the number of optional substituents,when present, to be 1, 2 or 3.

The term “comprising” when used in the specification includes“consisting of”.

If within the present text any item is referred to as “as mentionedherein”, it means that it may be mentioned anywhere in the present text.

The terms as mentioned in the present text have the following meanings:

The term “halogen” means a fluorine, chlorine, bromine or iodine,particularly a fluorine, chlorine or bromine atom.

The term “C₂-C₈-alkyl” means a linear or branched, saturated, monovalenthydrocarbon group having 2, 3, 4, 5, 6, 7 or 8 carbon atoms, e.g. aethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl, tert-butyl,pentyl, isopentyl, 2-methylbutyl, 1-methylbutyl, 1-ethylpropyl,1,2-dimethylpropyl, neo-pentyl, 1,1-dimethylpropyl, hexyl,1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl,1-ethylbutyl, 2-ethylbutyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl,3,3-dimethylbutyl, 2,3-dimethylbutyl, 1,2-dimethylbutyl,1,3-dimethylbutyl, 3-ethyl-pentyl or 3-ethyl-hexyl group, or an isomerthereof. Particularly, said group has 2, 3 or 4 carbon atoms(“C₂-C₄-alkyl”), e.g. a ethyl, propyl, isopropyl, butyl, sec-butylisobutyl, or tert-butyl group, more particularly 2 or 3 carbon atoms(“C₂-C₃-alkyl”), e.g. a ethyl, n-propyl or isopropyl group.

The term “C₂-C₈-hydroxyalkyl” means a linear or branched, saturated,monovalent hydrocarbon group in which the term “C₂-C₈-alkyl” is definedsupra, and in which 1 or 2 hydrogen atoms are replaced with a hydroxygroup, e.g. a 1-hydroxyethyl, 2-hydroxyethyl, 1,2-dihydroxyethyl,3-hydroxypropyl, 2-hydroxypropyl, 1-hydroxypropyl, 1-hydroxypropan-2-yl,2-hydroxypropan-2-yl, 2,3-dihydroxypropyl, 1,3-dihydroxypropan-2-yl,3-hydroxy-2-methyl-propyl, 2-hydroxy-2-methyl-propyl,1-hydroxy-2-methyl-propyl, 3-ethyl-2-hydroxypentyl or3-ethyl-2-hydroxyhexyl group.

The term “C₁-C₄-alkoxy” means a linear or branched, saturated,monovalent group of formula (C₁-C₄-alkyl)-O—, which means methoxy,ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, isobutoxy ortert-butoxy.

The term “C₃-C₆-cycloalkyl” means a saturated, monovalent, monocyclichydrocarbon ring which contains 3, 4, 5 or 6 carbon atoms(“C₃-C₆-cycloalkyl”). Said C₃-C₆-cycloalkyl group is a monocyclichydrocarbon ring, e.g. a cyclopropyl, cyclobutyl, cyclopentyl orcyclohexyl.

The term “5- to 6-membered heterocycloalkyl” means a monocyclic,saturated heterocycle with 5 or 6 ring atoms in total, which contains aheteroatom-containing group selected from the group consisting of—NR¹¹—, —O—, —S—, —SO—, —SO₂—, —SO₂—NR¹¹—, —SO(═NR¹¹)—, wherein R¹¹means a hydrogen atom or a C₁-C₃-alkyl group. It being possible for saidheterocycloalkyl group to be attached to the rest of the molecule viaany one of the carbon atoms or, if present, a nitrogen atom.

Said heterocycloalkyl group, without being limited thereto, can be a5-membered ring, such as tetrahydrofuranyl, 1,3-dioxolanyl, thiolanyl,pyrrolidinyl, imidazolidinyl, pyrazolidinyl, 1,1-dioxidothiolanyl,1,2-oxazolidinyl, 1,3-oxazolidinyl or 1,3-thiazolidinyl,tetrahydrothiophene 1-oxide, 1,2-thiazolidine 1-oxide, 1,3-thiazolidine1-oxide, tetrahydrothiophene 1,1-dioxide, 1,2-thiazolidine 1,1-dioxide,1,3-thiazolidine 1,1-dioxide, 1,2,5-thiadiazolidine 1,1-dioxide,1,2,4-thiadiazolidine 1,1-dioxide, 1,2,3-thiadiazolidine 1,1-dioxide,tetrahydro-1H-1λ⁴-thiophen-1-imine 1-oxide, 1λ⁴,2-thiazolidin-1-imine1-oxide or 1λ⁴,3-thiazolidin-1-imine 1-oxide, for example; or a 6membered ring, such as tetrahydropyranyl, tetrahydrothiopyranyl,piperidinyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl,1,3-dioxanyl, 1,4-dioxanyl or 1,2-oxazinanyl, tetrahydro-2H-thiopyran1-oxide, 1,2-thiazinane 1-oxide, 1,3-thiazinane 1-oxide, thiomorpholine1-oxide, tetrahydro-2H-thiopyran 1,1-dioxide, 1,2-thiazinane1,1-dioxide, 1,3-thiazinane 1,1-dioxide, thiomorpholine 1,1-dioxide,1,2,6-thiadiazinane 1,1-dioxide, 1,2,5-thiadiazinane 1,1-dioxide,1,2,4-thiadiazinane 1,1-dioxide, 1,2,3-thiadiazinane 1,1-dioxide,hexahydro-1λ⁴-thiopyran-1-imine 1-oxide, 1λ⁴,2-thiazinan-1-imine1-oxide, 1λ⁴,3-thiazinan-1-imine 1-oxide or 1λ⁴-thiomorpholin-1-imine1-oxide, for example.

The term “monocyclic heteroaryl” means a monovalent, aromatic ringhaving 5 or 6 ring atoms (a “5- or 6-membered heteroaryl” group), whichcontains at least one ring heteroatom and optionally one or two furtherring heteroatoms from the series: N, O and/or S, and which is bound viaa ring carbon atom or optionally via a ring nitrogen atom (if allowed byvalency).

Said heteroaryl group can be a 5-membered heteroaryl group, such as, forexample, thienyl, furanyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl,pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl,thiadiazolyl or tetrazolyl; or a 6-membered heteroaryl group, such as,for example, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl ortriazinyl.

In general, and unless otherwise mentioned, the heteroaryl orheteroarylene groups include all possible isomeric forms thereof, e.g.:tautomers and positional isomers with respect to the point of linkage tothe rest of the molecule. Thus, for some illustrative non-restrictingexamples, the term pyridinyl includes pyridin-2-yl, pyridin-3-yl andpyridin-4-yl; or the term thienyl includes thien-2-yl and thien-3-yl.

Where the plural form of the word compounds, salts, polymorphs,hydrates, solvates and the like, is used herein, this is taken to meanalso a single compound, salt, polymorph, isomer, hydrate, solvate or thelike.

By “stable compound” or “stable structure” is meant a compound that issufficiently robust to survive isolation to a useful degree of purityfrom a reaction mixture, and formulation into an efficacious therapeuticagent.

The compounds of the present invention optionally contain one or moreasymmetric centres, depending upon the location and nature of thevarious substituents desired. It is possible that one or more asymmetriccarbon atoms are present in the (R) or (S) configuration, which canresult in racemic mixtures in the case of a single asymmetric centre,and in diastereomeric mixtures in the case of multiple asymmetriccentres. In certain instances, it is possible that asymmetry also bepresent due to restricted rotation about a given bond, for example, thecentral bond adjoining two substituted aromatic rings of the specifiedcompounds.

Preferred compounds are those which produce the more desirablebiological activity. Separated, pure or partially purified isomers andstereoisomers or racemic or diastereomeric mixtures of the compounds ofthe present invention are also included within the scope of the presentinvention. The purification and the separation of such materials can beaccomplished by standard techniques known in the art.

Preferred isomers are those which produce the more desirable biologicalactivity. These separated, pure or partially purified isomers or racemicmixtures of the compounds of this invention are also included within thescope of the present invention. The purification and the separation ofsuch materials can be accomplished by standard techniques known in theart.

The optical isomers can be obtained by resolution of the racemicmixtures according to conventional processes, for example, by theformation of diastereoisomeric salts using an optically active acid orbase or formation of covalent diastereomers. Examples of appropriateacids are tartaric, diacetyltartaric, ditoluoyltartaric andcamphorsulfonic acid. Mixtures of diastereoisomers can be separated intotheir individual diastereomers on the basis of their physical and/orchemical differences by methods known in the art, for example, bychromatography or fractional crystallisation. The optically active basesor acids are then liberated from the separated diastereomeric salts. Adifferent process for separation of optical isomers involves the use ofchiral chromatography (e.g., HPLC columns using a chiral phase), with orwithout conventional derivatisation, optimally chosen to maximise theseparation of the enantiomers. Suitable HPLC columns using a chiralphase are commercially available, such as those manufactured by Daicel,e.g., Chiracel OD and Chiracel OJ, for example, among many others, whichare all routinely selectable. Enzymatic separations, with or withoutderivatisation, are also useful. The optically active compounds of thepresent invention can likewise be obtained by chiral syntheses utilizingoptically active starting materials.

In order to distinguish different types of isomers from each otherreference is made to IUPAC Rules Section E (Pure Appl Chem 45, 11-30,1976).

The present invention includes all possible stereoisomers of thecompounds of the present invention as single stereoisomers, or as anymixture of said stereoisomers, e.g. (R)- or (S)-isomers, in any ratio.Isolation of a single stereoisomer, e.g. a single enantiomer or a singlediastereomer, of a compound of the present invention is achieved by anysuitable state of the art method, such as chromatography, especiallychiral chromatography, for example.

Further, the compounds of the present invention can exist as N-oxides,which are defined in that at least one nitrogen of the compounds of thepresent invention is oxidised. The present invention includes all suchpossible N-oxides.

The present invention also covers useful forms of the compounds of thepresent invention, such as metabolites, hydrates, solvates, prodrugs,salts, in particular pharmaceutically acceptable salts, and/orco-precipitates.

The compounds of the present invention can exist as a hydrate, or as asolvate, wherein the compounds of the present invention contain polarsolvents, in particular water, methanol or ethanol for example, asstructural element of the crystal lattice of the compounds. It ispossible for the amount of polar solvents, in particular water, to existin a stoichiometric or non-stoichiometric ratio. In the case ofstoichiometric solvates, e.g. a hydrate, hemi-, (semi-), mono-, sesqui-,di-, tri-, tetra-, penta- etc. solvates or hydrates, respectively, arepossible. The present invention includes all such hydrates or solvates.

Further, it is possible for the compounds of the present invention toexist in free form, e.g. as a free base, or as a free acid, or as azwitterion, or to exist in the form of a salt. Said salt may be anysalt, either an organic or inorganic addition salt, particularly anypharmaceutically acceptable organic or inorganic addition salt, which iscustomarily used in pharmacy, or which is used, for example, forisolating or purifying the compounds of the present invention.

The term “pharmaceutically acceptable salt” refers to an inorganic ororganic acid addition salt of a compound of the present invention. Forexample, see S. M. Berge, et al. “Pharmaceutical Salts,” J. Pharm. Sci.1977, 66, 1-19.

A suitable pharmaceutically acceptable salt of the compounds of thepresent invention may be, for example, an acid-addition salt of acompound of the present invention bearing a nitrogen atom, in a chain orin a ring, for example, which is sufficiently basic, such as anacid-addition salt with an inorganic acid, or “mineral acid”, such ashydrochloric, hydrobromic, hydroiodic, sulfuric, sulfamic, bisulfuric,phosphoric, or nitric acid, for example, or with an organic acid, suchas formic, acetic, acetoacetic, pyruvic, trifluoroacetic, propionic,butyric, hexanoic, heptanoic, undecanoic, lauric, benzoic, salicylic,2-(4-hydroxybenzoyl)-benzoic, camphoric, cinnamic,cyclopentanepropionic, digluconic, 3-hydroxy-2-naphthoic, nicotinic,pamoic, pectinic, 3-phenylpropionic, pivalic, 2-hydroxyethanesulfonic,itaconic, trifluoromethanesulfonic, dodecylsulfuric, ethanesulfonic,benzenesulfonic, para-toluenesulfonic, methanesulfonic,2-naphthalenesulfonic, naphthalinedisulfonic, camphorsulfonic acid,citric, tartaric, stearic, lactic, oxalic, malonic, succinic, malic,adipic, alginic, maleic, fumaric, D-gluconic, mandelic, ascorbic,glucoheptanoic, glycerophosphoric, aspartic, sulfosalicylic, orthiocyanic acid, for example.

Further, another suitably pharmaceutically acceptable salt of a compoundof the present invention which is sufficiently acidic, is an alkalimetal salt, for example a sodium or potassium salt, an alkaline earthmetal salt, for example a calcium, magnesium or strontium salt, or analuminium or a zinc salt, or an ammonium salt derived from ammonia orfrom an organic primary, secondary or tertiary amine having 1 to 20carbon atoms, such as ethylamine, diethylamine, triethylamine,ethyldiisopropylamine, monoethanolamine, diethanolamine,triethanolamine, dicyclohexylamine, dimethylaminoethanol,diethylaminoethanol, tris(hydroxymethyl)aminomethane, procaine,dibenzylamine, N-methylmorpholine, arginine, lysine,1,2-ethylenediamine, N-methylpiperidine, N-methyl-glucamine,N,N-dimethyl-glucamine, N-ethyl-glucamine, 1,6-hexanediamine,glucosamine, sarcosine, serinol, 2-amino-1,3-propanediol,3-amino-1,2-propanediol, 4-amino-1,2,3-butanetriol, or a salt with aquarternary ammonium ion having 1 to 20 carbon atoms, such astetramethylammonium, tetraethylammonium, tetra(n-propyl)ammonium,tetra(n-butyl)ammonium, N-benzyl-N,N,N-trimethylammonium, choline orbenzalkonium.

Those skilled in the art will further recognise that it is possible foracid addition salts of the claimed compounds to be prepared by reactionof the compounds with the appropriate inorganic or organic acid via anyof a number of known methods. Alternatively, alkali and alkaline earthmetal salts of acidic compounds of the present invention are prepared byreacting the compounds of the present invention with the appropriatebase via a variety of known methods.

The present invention includes all possible salts of the compounds ofthe present invention as single salts, or as any mixture of said salts,in any ratio.

In the present text, in particular in the Experimental Section, for thesynthesis of intermediates and of examples of the present invention,when a compound is mentioned as a salt form with the corresponding baseor acid, the exact stoichiometric composition of said salt form, asobtained by the respective preparation and/or purification process, is,in most cases, unknown. Unless specified otherwise, suffixes to chemicalnames or structural formulae relating to salts, such as “hydrochloride”,“trifluoroacetate”, “sodium salt”, or “×HCl”, “×CF₃COOH”, “×Na⁺”, forexample, mean a salt form, the stoichiometry of which salt form notbeing specified.

This applies analogously to cases in which synthesis intermediates orexample compounds or salts thereof have been obtained, by thepreparation and/or purification processes described, as solvates, suchas hydrates, with (if defined) unknown stoichiometric composition.

Furthermore, the present invention includes all possible crystallineforms, or polymorphs, of the compounds of the present invention, eitheras single polymorph, or as a mixture of more than one polymorph, in anyratio.

Moreover, the present invention also includes prodrugs of the compoundsaccording to the invention. The term “prodrugs” here designatescompounds which themselves can be biologically active or inactive, butare converted (for example metabolically or hydrolytically) intocompounds according to the invention during their residence time in thebody.

The invention further includes all possible crystallized and polymorphicforms of the inventive compounds, whereby the polymorphs are existingeither as a single polymorph form or are existing as a mixture ofseveral polymorphs in all concentrations.

The compounds are either commercially available or can be preparedaccording to procedures available from the public domain, asunderstandable to the person skilled in the art. Specific examples aredescribed in the Experimental Section.

In accordance with a second embodiment of the first aspect, the presentinvention covers compounds of general formula (I), supra, in which:

-   X represents CH or N;-   Y represents CR³ or N;-   Z represents CH or N, wherein    -   if X represents N, Y represents CR³ and Z represents CH, and    -   if X represents CH, Z represents CH and Y represents CR³ or N,        and    -   if Z represents N, Y represents N and X represents CH;-   R¹ represents C₂-C₈-hydroxyalkyl, wherein said C₂-C₈-hydroxyalkyl    groups are optionally substituted once with R⁷ and optionally one to    three times with halogen, or    -   C₃-C₆-cycloalkyl substituted once with hydroxy or        C₁-C₃-hydroxyalkyl and optionally one to three times with        halogen, or    -   (C₃-C₆-cycloalkyl substituted once with hydroxy)-C₁-C₄-alkyl, or    -   5- to 6-membered heterocycloalkyl which contains a        heteroatom-containing group selected from the group consisting        of —NR¹¹—, —O— or —S— substituted once with hydroxy or    -   C₁-C₃-hydroxyalkyl and optionally one to three times with        halogen, or    -   5- to 6-membered heterocycloalkyl which contains a        heteroatom-containing group selected from the group consisting        of —SO—, —SO₂—, —SO₂—NR¹¹— or —SO(═NR¹¹)— optionally substituted        once with hydroxy or C₁-C₃-hydroxyalkyl and optionally one to        three times with halogen, or    -   (5- to 6-membered heterocycloalkyl optionally substituted once        with hydroxy)-C₁-C₄-alkyl;-   R² represents hydrogen, chloro, methyl, fluoromethyl,    difluoromethyl, trifluoromethyl, methoxy, difluoromethoxy,    trifluoromethoxy or —NR⁸R⁹;-   R³ represents hydrogen, halogen or methyl;-   R⁴ represents hydrogen, methyl, fluoromethyl, difluoromethyl,    trifluoromethyl, methoxy, halogen or cyano;-   R⁵ represents hydrogen, halogen, methyl, fluoromethyl,    difluoromethyl, trifluoromethyl, methoxy, difluoromethoxy or    trifluoromethoxy;-   R⁶ represents hydrogen or halogen;-   R⁷ represents C₁-C₄-alkoxy, —CO₂—R¹⁰, —CO—NR⁸R⁹, cyano, —NR⁸R⁹,    C₃-C₆-cycloalkyl, 5- to 6-membered heterocycloalkyl, phenyl or    monocyclic heteroaryl;-   R⁸ and R⁹ are the same or different and represent, independently    from each other, hydrogen or C₁-C₃-alkyl, or    -   together with the nitrogen atom to which they are attached form        a 4- to 6-membered nitrogen containing heterocyclic ring, said        ring optionally containing one additional heteroatom selected        from O, S, NH, NR^(a) in which R^(a) represents a C₁-C₄-alkyl        group;-   R¹⁰ represents hydrogen or C₁-C₄-alkyl;-   R¹¹ represents hydrogen or C₁-C₃-alkyl;    their polymorphs, enantiomeres, diastereomeres, racemates,    tautomeres, N-oxides, hydrates and solvates, as well as their    physiological acceptable salts and solvates of these salts, as well    as mixtures of the same.

In accordance with a third embodiment of the first aspect, the presentinvention covers compounds of general formula (I), supra, in which:

-   X represents CH;-   Y represents CR³;-   Z represents CH;-   R¹ represents C₂-C₆-hydroxyalkyl, wherein said C₂-C₆-hydroxyalkyl    groups are optionally substituted once with cyclobutyl and    optionally one to three times with fluoro, or    -   C₄-C₆-cycloalkyl substituted once with hydroxy and optionally        one to two times with fluoro, or    -   (C₄-C₆-cycloalkyl substituted once with hydroxy)-methyl, or        4-hydroxyoxolan-3-yl;-   R² represents hydrogen, chloro, trifluoromethyl or trifluoromethoxy;-   R³ represents hydrogen or fluoro;-   R⁴ represents hydrogen, fluoro, chloro, cyano, methyl,    trifluoromethyl or methoxy;-   R⁵ represents hydrogen, fluoro, chloro, bromo, difluoromethyl,    trifluoromethyl, methoxy or trifluoromethoxy;-   R⁶ represents hydrogen, fluoro or chloro;    their polymorphs, enantiomeres, diastereomeres, racemates,    tautomeres, N-oxides, hydrates and solvates, as well as their    physiological acceptable salts and solvates of these salts, as well    as mixtures of the same.

In accordance with a forth embodiment of the first aspect, the presentinvention covers compounds of general formula (I), supra, in which:

-   X represents CH;-   Y represents CR³;-   Z represents CH;-   R¹ represents C₂-C₄-hydroxyalkyl;-   R² represents hydrogen, chloro, trifluoromethyl or trifluoromethoxy;-   R³ represents hydrogen or fluoro;-   R⁴ represents hydrogen or fluoro;-   R⁵ represents hydrogen, chloro, trifluoromethyl or trifluoromethoxy;-   R⁶ represents hydrogen;    their polymorphs, enantiomeres, diastereomeres, racemates,    tautomeres, N-oxides, hydrates and solvates, as well as their    physiological acceptable salts and solvates of these salts, as well    as mixtures of the same.

In accordance with a second aspect, the present invention covers methodsof preparing compounds of general formula (I) as defined supra, saidmethods comprising the step of allowing an intermediate compound ofgeneral formula (VII):

in which

-   X represents CH or N;-   Y represents CR³ or N;-   Z represents CH or N, wherein    -   if X represents N, Y represents CR³ and Z represents CH, and    -   if X represents CH, Z represents CH and Y represents CR³ or N,        and    -   if Z represents N, Y represents N and X represents CH;-   R² represents hydrogen, chloro, methyl, fluoromethyl,    difluoromethyl, trifluoromethyl, methoxy, difluoromethoxy,    trifluoromethoxy or —NR⁸R⁹;-   R³ represents hydrogen, halogen or methyl;-   R⁴ represents hydrogen, methyl, fluoromethyl, difluoromethyl,    trifluoromethyl, methoxy, halogen or cyano;-   R⁵ represents hydrogen, halogen, methyl, fluoromethyl,    difluoromethyl, trifluoromethyl, methoxy, difluoromethoxy or    trifluoromethoxy;-   R⁶ represents hydrogen or halogen;-   R⁸ and R⁹ are the same or different and represent, independently    from each other, hydrogen or C₁-C₃-alkyl, or    -   together with the nitrogen atom to which they are attached form        a 4- to 6-membered nitrogen containing heterocyclic ring, said        ring optionally containing one additional heteroatom selected        from O, S, NH, NR^(a) in which R^(a) represents a C₁-C₄-alkyl        group;        to react with a compound of general formula (VIII):

H₂N—R¹  (VIII),

in which

-   R¹ represents C₂-C₈-hydroxyalkyl, wherein said C₂-C₈-hydroxyalkyl    groups are optionally substituted once with R⁷ and optionally one to    three times with halogen, or    -   C₃-C₆-cycloalkyl substituted once with hydroxy or        C₁-C₃-hydroxyalkyl and optionally one to three times with        halogen, or    -   (C₃-C₆-cycloalkyl substituted once with hydroxy)-C₁-C₄-alkyl, or    -   5- to 6-membered heterocycloalkyl substituted once with hydroxy        or C₁-C₃-hydroxyalkyl and optionally one to three times with        halogen, or    -   (5- to 6-membered heterocycloalkyl substituted once with        hydroxy)-C₁-C₄-alkyl, in which R⁷ is as defined supra.        thereby giving a compound of general formula (I):

in which X, Y, Z, R¹, R², R⁴, R⁵ and R⁶ are as defined supra.

The present invention covers methods of preparing compounds of thepresent invention of general formula (I), said methods comprising thesteps as described in the Experimental Section herein.

In accordance with a third aspect, the present invention coversintermediate compounds which are useful for the preparation of thecompounds of general formula (I), supra.

Particularly, the inventions covers the intermediate compounds ofgeneral formula (VII):

in which

-   X represents CH or N;-   Y represents CR³ or N;-   Z represents CH or N, wherein    -   if X represents N, Y represents CR³ and Z represents CH, and    -   if X represents CH, Z represents CH and Y represents CR³ or N,        and    -   if Z represents N, Y represents N and X represents CH;-   R² represents hydrogen, chloro, methyl, fluoromethyl,    difluoromethyl, trifluoromethyl, methoxy, difluoromethoxy,    trifluoromethoxy or —NR⁸R⁹;-   R³ represents hydrogen, halogen or methyl;-   R⁴ represents hydrogen, methyl, fluoromethyl, difluoromethyl,    trifluoromethyl, methoxy, halogen or cyano;-   R⁵ represents hydrogen, halogen, methyl, fluoromethyl,    difluoromethyl, trifluoromethyl, methoxy, difluoromethoxy or    trifluoromethoxy;-   R⁶ represents hydrogen or halogen;-   R⁸ and R⁹ are the same or different and represent, independently    from each other, hydrogen or C₁-C₃-alkyl, or    -   together with the nitrogen atom to which they are attached form        a 4- to 6-membered nitrogen containing heterocyclic ring, said        ring optionally containing one additional heteroatom selected        from O, S, NH, NR^(a) in which R^(a) represents a C₁-C₄-alkyl        group;

In accordance with a forth aspect, the present invention covers the useof said intermediate compounds for the preparation of a compound ofgeneral formula (I) as defined supra. Particularly, the inventionscovers the use of intermediate compounds of general formula (VII):

in which

-   X represents CH or N;-   Y represents CR³ or N;-   Z represents CH or N, wherein    -   if X represents N, Y represents CR³ and Z represents CH, and    -   if X represents CH, Z represents CH and Y represents CR³ or N,        and    -   if Z represents N, Y represents N and X represents CH;-   R² represents hydrogen, chloro, methyl, fluoromethyl,    difluoromethyl, trifluoromethyl, methoxy, difluoromethoxy,    trifluoromethoxy or —NR⁸R⁹;-   R³ represents hydrogen, halogen or methyl;-   R⁴ represents hydrogen, methyl, fluoromethyl, difluoromethyl,    trifluoromethyl, methoxy, halogen or cyano;-   R⁵ represents hydrogen, halogen, methyl, fluoromethyl,    difluoromethyl, trifluoromethyl, methoxy, difluoromethoxy or    trifluoromethoxy;-   R⁶ represents hydrogen or halogen;-   R⁸ and R⁹ are the same or different and represent, independently    from each other, hydrogen or C₁-C₃-alkyl, or    -   together with the nitrogen atom to which they are attached form        a 4- to 6-membered nitrogen containing heterocyclic ring, said        ring optionally containing one additional heteroatom selected        from O, S, NH, NR^(a) in which R^(a) represents a C₁-C₄-alkyl        group;        for the preparation of a compound of general formula (I) as        defined supra.

The present invention covers the intermediate compounds which aredisclosed in the Example Section of this text, infra.

In a further embodiment of the first aspect, the present inventioncovers compounds of formula (I), supra, in which:

-   R¹ represents C₂-C₈-hydroxyalkyl, wherein said C₂-C₈-hydroxyalkyl    groups are optionally substituted once with R⁷ and optionally one to    three times with halogen, or    -   C₃-C₆-cycloalkyl substituted once with hydroxy or        C₁-C₃-hydroxyalkyl and optionally one to three times with        halogen, or    -   (C₃-C₆-cycloalkyl substituted once with hydroxy)-C₁-C₄-alkyl, or    -   5- to 6-membered heterocycloalkyl optionally substituted once        with hydroxy or C₁-C₃-hydroxyalkyl and optionally one to three        times with halogen, or    -   (5- to 6-membered heterocycloalkyl optionally substituted once        with hydroxy)-C₁-C₄-alkyl;        their polymorphs, enantiomeres, diastereomeres, racemates,        tautomeres, N-oxides, hydrates and solvates, as well as their        physiological acceptable salts and solvates of these salts, as        well as mixtures of the same.

In a further embodiment of the first aspect, the present inventioncovers compounds of formula (I), supra, in which:

-   R¹ represents C₂-C₈-hydroxyalkyl, wherein said C₂-C₈-hydroxyalkyl    groups are optionally substituted once with R⁷ and optionally one to    three times with halogen, or    -   C₃-C₆-cycloalkyl substituted once with hydroxy or        C₁-C₃-hydroxyalkyl and optionally one to three times with        halogen, or    -   (C₃-C₆-cycloalkyl substituted once with hydroxy)-C₁-C₄-alkyl, or    -   5- to 6-membered heterocycloalkyl which contains a        heteroatom-containing group selected from the group consisting        of —NR⁸—, —O— or —S— substituted once with hydroxy or        C₁-C₃-hydroxyalkyl and optionally one to three times with        halogen, or    -   5- to 6-membered heterocycloalkyl which contains a        heteroatom-containing group selected from the group consisting        of —SO—, —SO₂—, —SO₂—NR⁸— or —SO(═NR⁸)— optionally substituted        once with hydroxy or C₁-C₃-hydroxyalkyl and optionally one to        three times with halogen, or    -   (5- to 6-membered heterocycloalkyl optionally substituted once        with hydroxy)-C₁-C₄-alkyl;        their polymorphs, enantiomeres, diastereomeres, racemates,        tautomeres, N-oxides, hydrates and solvates, as well as their        physiological acceptable salts and solvates of these salts, as        well as mixtures of the same.

In a further embodiment of the first aspect, the present inventioncovers compounds of formula (I), supra, in which:

-   R¹ represents C₂-C₈-hydroxyalkyl, wherein said C₂-C₈-hydroxyalkyl    groups are optionally substituted once with R⁷ and optionally one to    three times with halogen, or    -   C₃-C₆-cycloalkyl substituted once with hydroxy or        C₁-C₃-hydroxyalkyl and optionally one to three times with        halogen, or    -   (C₃-C₆-cycloalkyl substituted once with hydroxy)-C₁-C₄-alkyl;        their polymorphs, enantiomeres, diastereomeres, racemates,        tautomeres, N-oxides, hydrates and solvates, as well as their        physiological acceptable salts and solvates of these salts, as        well as mixtures of the same.

In a further embodiment of the first aspect, the present inventioncovers compounds of formula (I), supra, in which:

-   R¹ represents C₂-C₆-hydroxyalkyl, wherein said C₂-C₆-hydroxyalkyl    groups are optionally substituted once with cyclobutyl and    optionally one to three times with fluoro, or    -   C₄-C₆-cycloalkyl substituted once with hydroxy and optionally        one to two times with fluoro, or    -   (C₄-C₆-cycloalkyl substituted once with hydroxy)-methyl, or        4-hydroxyoxolan-3-yl;        their polymorphs, enantiomeres, diastereomeres, racemates,        tautomeres, N-oxides, hydrates and solvates, as well as their        physiological acceptable salts and solvates of these salts, as        well as mixtures of the same.

In a further embodiment of the first aspect, the present inventioncovers compounds of formula (I), supra, in which:

-   R¹ represents 5- to 6-membered heterocycloalkyl which contains a    heteroatom-containing group selected from the group consisting of    —NR⁸—, —O— or —S— substituted once with hydroxy or    C₁-C₃-hydroxyalkyl and optionally one to three times with halogen;    their polymorphs, enantiomeres, diastereomeres, racemates,    tautomeres, N-oxides, hydrates and solvates, as well as their    physiological acceptable salts and solvates of these salts, as well    as mixtures of the same.

In a further embodiment of the first aspect, the present inventioncovers compounds of formula (I), supra, in which:

-   R¹ represents 5- to 6-membered heterocycloalkyl which contains a    heteroatom-containing group selected from the group consisting of    —SO—, —SO₂—, —SO₂—NR⁸— or —SO(═NR⁸)— optionally substituted once    with hydroxy or C₁-C₃-hydroxyalkyl and optionally one to three times    with halogen;    their polymorphs, enantiomeres, diastereomeres, racemates,    tautomeres, N-oxides, hydrates and solvates, as well as their    physiological acceptable salts and solvates of these salts, as well    as mixtures of the same.

In a further embodiment of the first aspect, the present inventioncovers compounds of formula (I), supra, in which:

-   R¹ represents (5- to 6-membered heterocycloalkyl optionally    substituted once with hydroxy)-C₁-C₄-alkyl;    their polymorphs, enantiomeres, diastereomeres, racemates,    tautomeres, N-oxides, hydrates and solvates, as well as their    physiological acceptable salts and solvates of these salts, as well    as mixtures of the same.

In a particular further embodiment of the first aspect, the presentinvention covers combinations of two or more of the above mentionedembodiments under the heading “further embodiments of the first aspectof the present invention”.

The present invention covers any sub-combination within any embodimentor aspect of the present invention of intermediate compounds of generalformula (VII), supra.

The compounds of general formula (I) of the present invention can beconverted to any salt, preferably pharmaceutically acceptable salts, asdescribed herein, by any method which is known to the person skilled inthe art. Similarly, any salt of a compound of general formula (I) of thepresent invention can be converted into the free compound, by any methodwhich is known to the person skilled in the art.

The compounds according to the invention of general formula (I) can beprepared according to the following scheme 1. The scheme and proceduresdescribed below illustrate synthetic routes to the compounds of generalformula (I) of the invention and are not intended to be limiting. It isclear to the person skilled in the art that the order of transformationsas exemplified in scheme 1 can be modified in various ways. The order oftransformations exemplified in this scheme is therefore not intended tobe limiting. In addition, interconversion of any of the substituents R¹,R², R³, R⁴, R⁵ or R⁶ can be achieved before and/or after the exemplifiedtransformations. These modifications can be such as the introduction ofprotecting groups, cleavage of protecting groups, reduction or oxidationof functional groups, halogenation, metallation, metal-catalysedcoupling reactions, substitution or other reactions known to the personskilled in the art. These transformations include those which introducea functionality which allows for further interconversion ofsubstituents. Appropriate protecting groups and their introduction andcleavage are well-known to the person skilled in the art. Specificexamples are described in the subsequent paragraphs.

Scheme 1 shows a route for the preparation of compounds of generalformula (I) in which X, Y, Z, R¹, R², R³, R⁴, R⁵ and R⁶ have the meaningas given for the general formula (I) supra. Dichloropyrimidinecarboxylates can be coupled in a Suzuki cross coupling reaction withboronic acids/esters of formula (III) in order to provide non-commercialcompounds of formula (IV). This reaction can be performed usingappropriate palladium catalysts, such as Pd(PPh₃)₄ or Xphosprecatalysts, in the presence or absence of phosphine ligands, a base,such as potassium carbonate or sodium carbonate, in a solvent such asTHF, DMF, dioxane or toluene, and in the presence or absence of water.

Conversion to the carboxylic acids of formula (V) can be achieved usingaqueous bases such as NaOH or LiOH.

Compounds of formula (VII) can be prepared in an analogous fashion ascompounds of formula (IV) via a Suzuki cross coupling reaction withboronic acids/esters of formula (VI).

Compounds of general formula (I) can then be synthesised through anamine coupling using an amine of formula (VIII). This reaction can beperformed using reagents such as HATU or T3P, in the presence of a basesuch as NaHCO₃, Na₂CO₃, K₂CO₃ or DIPEA in solvents like dioxane, THF,DMF or NMP. Optionally this amide coupling can also be made via the acylchloride or the anhydride derivatives of compounds (VII).

Scheme 2 describes another route for the preparation of compounds orformula (I) using the same steps as in scheme 1 but in a differentorder.

Scheme 3 describes an alternative route to prepare compounds of generalformula (I). 2,6-Dichloropyrimidine-4-carboxylic acid can be reactedwith an amine of formula (VII) via an amid coupling reaction to providecompounds of formula (XI). This reaction can be performed using reagentssuch as HATU or T3P, in the presence of a base such as NaHCO₃, Na₂CO₃,K₂CO₃ or DIPEA in solvents like dioxane, THF, DMF or NMP. Two subsequentSuzuki cross coupling reactions using first a boronic acid/ester offormula (III) and then a boronic acid/ester of formula (VI) allow thepreparation of compounds of general formula (I). Such reactions can beperformed using palladium catalysts such as Pd(PPh₃)₄ or Xphosprecatalysts, in the presence or absence of phosphine ligands, a base,such as K₂CO₃, Na₂CO₃ or CsCO₃, in a solvent such as THF, DMF, dioxaneor toluene, and in the presence or absence of water.

Compounds of general formula (I) of the present invention demonstrate avaluable pharmacological spectrum of action, which could not have beenpredicted. Compounds of the present invention have surprisingly beenfound to effectively inhibit AHR and it is possible therefore that saidcompounds be used for the treatment or prophylaxis of diseases,preferably cancer or conditions with dysregulated immune responses orother disorders associated with aberrant AHR signaling, in humans andanimals.

Disorders and conditions particularly suitable for treatment with an AHRinhibitor of the present invention are liquid and solid tumours, such ascancers of the breast, respiratory tract, brain, reproductive organs,digestive tract, urinary tract, eye, liver, skin, head and neck,thyroid, parathyroid and their distant metastases. Those disorders alsoinclude lymphomas, sarcomas, and leukaemias.

Examples of breast cancers include, but are not limited to, triplenegative breast cancer, invasive ductal carcinoma, invasive lobularcarcinoma, ductal carcinoma in situ, and lobular carcinoma in situ.

Examples of cancers of the respiratory tract include, but are notlimited to, small-cell and non-small-cell lung carcinoma, as well asbronchial adenoma and pleuropulmonary blastoma.

Examples of brain cancers include, but are not limited to, brain stemand hypophtalmic glioma, cerebellar and cerebral astrocytoma,glioblastoma, medulloblastoma, ependymoma, as well as neuroectodermaland pineal tumour.

Tumours of the male reproductive organs include, but are not limited to,prostate and testicular cancer.

Tumours of the female reproductive organs include, but are not limitedto, endometrial, cervical, ovarian, vaginal, and vulvar cancer, as wellas sarcoma of the uterus.

Examples of ovarian cancer include, but are not limited to seroustumour, endometrioid tumour, mucinous cystadenocarcinoma, granulosa celltumour, Sertoli-Leydig cell tumour and arrhenoblastoma.

Examples of cervical cancer include, but are not limited to squamouscell carcinoma, adenocarcinoma, adenosquamous carcinoma, small cellcarcinoma, neuroendocrine tumour, glassy cell carcinoma andvilloglandular adenocarcinoma.

Tumours of the digestive tract include, but are not limited to, anal,colon, colorectal, esophageal, gallbladder, gastric, pancreatic, rectal,small-intestine, and salivary gland cancers. Examples of esophagealcancer include, but are not limited to esophageal cell carcinomas andadenocarcinomas, as well as squamous cell carcinomas, leiomyosarcoma,malignant melanoma, rhabdomyosarcoma and lymphoma.

Examples of gastric cancer include, but are not limited to intestinaltype and diffuse type gastric adenocarcinoma.

Examples of pancreatic cancer include, but are not limited to ductaladenocarcinoma, adenosquamous carcinomas and pancreatic endocrinetumours.

Tumours of the urinary tract include, but are not limited to, bladder,penile, kidney, renal pelvis, ureter, urethral and human papillary renalcancers.

Examples of kidney cancer include, but are not limited to renal cellcarcinoma, urothelial cell carcinoma, juxtaglomerular cell tumour(reninoma), angiomyolipoma, renal oncocytoma, Bellini duct carcinoma,clear-cell sarcoma of the kidney, mesoblastic nephroma and Wilms'tumour.

Examples of bladder cancer include, but are not limited to transitionalcell carcinoma, squamous cell carcinoma, adenocarcinoma, sarcoma andsmall cell carcinoma.

Eye cancers include, but are not limited to, intraocular melanoma andretinoblastoma.

Examples of liver cancers include, but are not limited to,hepatocellular carcinoma (liver cell carcinomas with or withoutfibrolamellar variant), cholangiocarcinoma (intrahepatic bile ductcarcinoma), and mixed hepatocellular cholangiocarcinoma.

Skin cancers include, but are not limited to, squamous cell carcinoma,Kaposi's sarcoma, malignant melanoma, Merkel cell skin cancer, andnon-melanoma skin cancer.

Head-and-neck cancers include, but are not limited to, squamous cellcancer of the head and neck, laryngeal, hypopharyngeal, nasopharyngeal,oropharyngeal cancer, salivary gland cancer, lip and oral cavity cancerand squamous cell.

Lymphomas include, but are not limited to, AIDS-related lymphoma,non-Hodgkin's lymphoma, cutaneous T-cell lymphoma, Burkitt lymphoma,Hodgkin's disease, and lymphoma of the central nervous system.

Sarcomas include, but are not limited to, sarcoma of the soft tissue,osteosarcoma, malignant fibrous histiocytoma, lymphosarcoma, andrhabdomyosarcoma.

Leukemias include, but are not limited to, acute myeloid leukemia, acutelymphoblastic leukemia, chronic lymphocytic leukemia, chronicmyelogenous leukemia, and hairy cell leukemia.

The term “treating” or “treatment” as stated throughout this document isused conventionally, for example the management or care of a subject forthe purpose of combating, alleviating, reducing, relieving, improvingthe condition of a disease or disorder, such as a carcinoma.

The compounds of the present invention can be used in particular intherapy and prevention, i.e. prophylaxis, of tumour growth andmetastases, especially in solid tumours of all indications and stageswith or without pre-treatment of the tumour growth.

Generally, the use of chemotherapeutic agents and/or anti-cancer agentsin combination with a compound or pharmaceutical composition of thepresent invention will serve to:

yield better efficacy in reducing the growth of a tumour or eveneliminate the tumour as compared to administration of either agentalone,provide for the administration of lesser amounts of the administeredchemotherapeutic agents, provide for a chemotherapeutic treatment thatis well tolerated in the patient with fewer deleterious pharmacologicalcomplications than observed with single agent chemotherapies and certainother combined therapies,provide for treating a broader spectrum of different cancer types inmammals, especially humans,provide for a higher response rate among treated patients,provide for a longer survival time among treated patients compared tostandard chemotherapy treatments,provide a longer time for tumour progression, and/oryield efficacy and tolerability results at least as good as those of theagents used alone, compared to known instances where other cancer agentcombinations produce antagonistic effects.

In addition, the compounds of general formula (I) of the presentinvention can also be used in combination with radiotherapy and/orsurgical intervention.

In a further embodiment of the present invention, the compounds ofgeneral formula (I) of the present invention may be used to sensitize acell to radiation, i.e. treatment of a cell with a compound of thepresent invention prior to radiation treatment of the cell renders thecell more susceptible to DNA damage and cell death than the cell wouldbe in the absence of any treatment with a compound of the presentinvention. In one aspect, the cell is treated with at least one compoundof general formula (I) of the present invention.

Thus, the present invention also provides a method of killing a cell,wherein a cell is administered one or more compounds of the presentinvention in combination with conventional radiation therapy.

The present invention also provides a method of rendering a cell moresusceptible to cell death, wherein the cell is treated with one or morecompounds of general formula (I) of the present invention prior to thetreatment of the cell to cause or induce cell death. In one aspect,after the cell is treated with one or more compounds of general formula(I) of the present invention, the cell is treated with at least onecompound, or at least one method, or a combination thereof, in order tocause DNA damage for the purpose of inhibiting the function of thenormal cell or killing the cell.

In other embodiments of the present invention, a cell is killed bytreating the cell with at least one DNA damaging agent, i.e. aftertreating a cell with one or more compounds of general formula (I) of thepresent invention to sensitize the cell to cell death, the cell istreated with at least one DNA damaging agent to kill the cell. DNAdamaging agents useful in the present invention include, but are notlimited to, chemotherapeutic agents (e.g. cis platin), ionizingradiation (X-rays, ultraviolet radiation), carcinogenic agents, andmutagenic agents.

In other embodiments, a cell is killed by treating the cell with atleast one method to cause or induce DNA damage. Such methods include,but are not limited to, activation of a cell signalling pathway thatresults in DNA damage when the pathway is activated, inhibiting of acell signalling pathway that results in DNA damage when the pathway isinhibited, and inducing a biochemical change in a cell, wherein thechange results in DNA damage. By way of a non-limiting example, a DNArepair pathway in a cell can be inhibited, thereby preventing the repairof DNA damage and resulting in an abnormal accumulation of DNA damage ina cell.

In one aspect of the invention, a compound of general formula (I) of thepresent invention is administered to a cell prior to the radiation orother induction of DNA damage in the cell. In another aspect of theinvention, a compound of general formula (I) of the present invention isadministered to a cell concomitantly with the radiation or otherinduction of DNA damage in the cell. In yet another aspect of theinvention, a compound of general formula (I) of the present invention isadministered to a cell immediately after radiation or other induction ofDNA damage in the cell has begun.

In another aspect, the cell is in vitro. In another embodiment, the cellis in vivo.

The compounds of the present invention can be administered as the solepharmaceutical agent or in combination with one or more otherpharmaceutically active ingredients where the combination causes nounacceptable adverse effects. The present invention also covers suchpharmaceutical combinations. For example, the compounds of the presentinvention can be combined with: 131l-chTNT, abarelix, abiraterone,aclarubicin, adalimumab, ado-trastuzumab emtansine, afatinib,aflibercept, aldesleukin, alectinib, alemtuzumab, alendronic acid,alitretinoin, altretamine, amifostine, aminoglutethimide, hexylaminolevulinate, amrubicin, amsacrine, anastrozole, ancestim, anetholedithiolethione, anetumab ravtansine, angiotensin II, antithrombin III,aprepitant, arcitumomab, arglabin, arsenic trioxide, asparaginase,atezolizumab, axitinib, azacitidine, basiliximab, belotecan,bendamustine, besilesomab, belinostat, bevacizumab, bexarotene,bicalutamide, bisantrene, bleomycin, blinatumomab, bortezomib,buserelin, bosutinib, brentuximab vedotin, busulfan, cabazitaxel,cabozantinib, calcitonine, calcium folinate, calcium levofolinate,capecitabine, capromab, carbamazepine carboplatin, carboquone,carfilzomib, carmofur, carmustine, catumaxomab, celecoxib, celmoleukin,ceritinib, cetuximab, chlorambucil, chlormadinone, chlormethine,cidofovir, cinacalcet, cisplatin, cladribine, clodronic acid,clofarabine, cobimetinib, copanlisib, crisantaspase, crizotinib,cyclophosphamide, cyproterone, cytarabine, dacarbazine, dactinomycin,daratumumab, darbepoetin alfa, dabrafenib, dasatinib, daunorubicin,decitabine, degarelix, denileukin diftitox, denosumab, depreotide,deslorelin, dianhydrogalactitol, dexrazoxane, dibrospidium chloride,dianhydrogalactitol, diclofenac, dinutuximab, docetaxel, dolasetron,doxifluridine, doxorubicin, doxorubicin+estrone, dronabinol, eculizumab,edrecolomab, elliptinium acetate, elotuzumab, eltrombopag, endostatin,enocitabine, enzalutamide, epirubicin, epitiostanol, epoetin alfa,epoetin beta, epoetin zeta, eptaplatin, eribulin, erlotinib,esomeprazole, estradiol, estramustine, ethinylestradiol, etoposide,everolimus, exemestane, fadrozole, fentanyl, filgrastim,fluoxymesterone, floxuridine, fludarabine, fluorouracil, flutamide,folinic acid, formestane, fosaprepitant, fotemustine, fulvestrant,gadobutrol, gadoteridol, gadoteric acid meglumine, gadoversetamide,gadoxetic acid, gallium nitrate, ganirelix, gefitinib, gemcitabine,gemtuzumab, Glucarpidase, glutoxim, GM-CSF, goserelin, granisetron,granulocyte colony stimulating factor, histamine dihydrochloride,histrelin, hydroxycarbamide, I-125 seeds, lansoprazole, ibandronic acid,ibritumomab tiuxetan, ibrutinib, idarubicin, ifosfamide, imatinib,imiquimod, improsulfan, indisetron, incadronic acid, ingenol mebutate,interferon alfa, interferon beta, interferon gamma, iobitridol,iobenguane (123I), iomeprol, ipilimumab, irinotecan, Itraconazole,ixabepilone, ixazomib, lanreotide, lansoprazole, lapatinib, lasocholine,lenalidomide, lenvatinib, lenograstim, lentinan, letrozole, leuprorelin,levamisole, levonorgestrel, levothyroxine sodium, lisuride, lobaplatin,lomustine, lonidamine, masoprocol, medroxyprogesterone, megestrol,melarsoprol, melphalan, mepitiostane, mercaptopurine, mesna, methadone,methotrexate, methoxsalen, methylaminolevulinate, methylprednisolone,methyltestosterone, metirosine, mifamurtide, miltefosine, miriplatin,mitobronitol, mitoguazone, mitolactol, mitomycin, mitotane,mitoxantrone, mogamulizumab, molgramostim, mopidamol, morphinehydrochloride, morphine sulfate, nabilone, nabiximols, nafarelin,naloxone+pentazocine, naltrexone, nartograstim, necitumumab, nedaplatin,nelarabine, neridronic acid, netupitant/palonosetron, nivolumab,pentetreotide, nilotinib, nilutamide, nimorazole, nimotuzumab,nimustine, nintedanib, nitracrine, nivolumab, obinutuzumab, octreotide,ofatumumab, olaparib, olaratumab, omacetaxine mepesuccinate, omeprazole,ondansetron, oprelvekin, orgotein, orilotimod, osimertinib, oxaliplatin,oxycodone, oxymetholone, ozogamicine, p53 gene therapy, paclitaxel,palbociclib, palifermin, palladium-103 seed, palonosetron, pamidronicacid, panitumumab, panobinostat, pantoprazole, pazopanib, pegaspargase,PEG-epoetin beta (methoxy PEG-epoetin beta), pembrolizumab,pegfilgrastim, peginterferon alfa-2b, pembrolizumab, pemetrexed,pentazocine, pentostatin, peplomycin, Perflubutane, perfosfamide,Pertuzumab, picibanil, pilocarpine, pirarubicin, pixantrone, plerixafor,plicamycin, poliglusam, polyestradiol phosphate,polyvinylpyrrolidone+sodium hyaluronate, polysaccharide-K, pomalidomide,ponatinib, porfimer sodium, pralatrexate, prednimustine, prednisone,procarbazine, procodazole, propranolol, quinagolide, rabeprazole,racotumomab, radium-223 chloride, radotinib, raloxifene, raltitrexed,ramosetron, ramucirumab, ranimustine, rasburicase, razoxane,refametinib, regorafenib, risedronic acid, rhenium-186 etidronate,rituximab, rolapitant, romidepsin, romiplostim, romurtide, roniciclib,samarium (153Sm) lexidronam, sargramostim, satumomab, secretin,siltuximab, sipuleucel-T, sizofiran, sobuzoxane, sodium glycididazole,sonidegib, sorafenib, stanozolol, streptozocin, sunitinib, talaporfin,talimogene laherparepvec, tamibarotene, tamoxifen, tapentadol,tasonermin, teceleukin, technetium (99mTc) nofetumomab merpentan,99mTc-HYNIC-[Tyr3]-octreotide, tegafur, tegafur+gimeracil+oteracil,temoporfin, temozolomide, temsirolimus, teniposide, testosterone,tetrofosmin, thalidomide, thiotepa, thymalfasin, thyrotropin alfa,tioguanine, tocilizumab, topotecan, toremifene, tositumomab,trabectedin, trametinib, tramadol, trastuzumab, trastuzumab emtansine,treosulfan, tretinoin, trifluridine+tipiracil, trilostane, triptorelin,trametinib, trofosfamide, thrombopoietin, tryptophan, ubenimex,valatinib, valrubicin, vandetanib, vapreotide, vemurafenib, vinblastine,vincristine, vindesine, vinflunine, vinorelbine, vismodegib, vorinostat,vorozole, yttrium-90 glass microspheres, zinostatin, zinostatinstimalamer, zoledronic acid, zorubicin.

The compounds of the invention can further be combined with otherreagents targeting the immune system, such as immune checkpointinhibitors. Compositions comprising a PD-1/-L1 axis antagonist and anAHR antagonist and methods of using the same are provided herein. Datapresented herein demonstrate that a combination of AHR inhibition andblockade of the PD-1/-L1 axis reduces the growth of tumor cells in morethan an additive manner. PD-1, along with its ligands PD-L1 and PD-L2,function as negative regulators of T cell activation. AHR suppressesimmune cell function while increasing cancer cell proliferation andmotility. PD-L1 is overexpressed in many cancers and overexpression ofPD-1 often occurs concomitantly in tumor infiltrating T cells. Thusresults in attenuation of T cell activation and evasion of immunesurveillance, which contributes to impaired antitumor immune responses.(Keir M E et al. (2008) Annu. Rev. Immunol. 26:677). Simultaneouslytargeting both the PD-1/-L1 axis and AHR enhances antitumor immuneresponses in more than an additive manner, leading to reduction of tumorgrowth that is unexpected. In some experiments, the resulting effect isgreater than the expected or calculated additive effect of theindividual components given separately. Thus, compositions comprising aPD-1/-L1 axis antagonist and an AHR antagonist are surprisinglyeffective in enhancing an immune response and in the treatment ofcancer.

In addition, the inventive compounds can also be used as a therapeuticin a variety of other disorders wherein AHR is involved such as,cardiovascular and lung diseases.

Accordingly, the compounds according to the invention are suitable forthe treatment and/or prophylaxis in particular of cardiovascular,inflammatory and fibrotic disorders and of renal disorders, inparticular of acute and chronic renal insufficiency, and also of acuteand chronic renal failure.

Accordingly, the compounds according to the invention can be used inmedicaments for the treatment and/or prophylaxis of cardiovascular,inflammatory and fibrotic disorders, renal disorders, in particular ofacute and chronic renal insufficiency, and also of acute and chronicrenal failure.

For the purpose of the present invention the term renal insufficiencycomprises both acute and chronic manifestations of renal insufficiency,and also underlying or related renal disorders such as diabetic andnon-diabetic nephropathies, hypertensive nephropathies, ischaemic renaldisorders, renal hypoperfusion, intradialytic hypotension, obstructiveuropathy, renal stenoses, glomerulopathies, glomerulonephritis (such as,for example, primary glomerulonephritides; minimal changeglomerulonephritis (lipoidnephrosis); membranous glomerulonephritis;focal segmental glomerulosclerosis (FSGS); membrane-proliferativeglomerulonephritis; crescentic glomerulonephritis; mesangioproliferativeglomerulonephritis (IgA nephritis, Berger's disease); post-infectiousglomerulonephritis; secondary glomerulonephritides: diabetes mellitus,lupus erythematosus, amyloidosis, Goodpasture syndrome, Wegenergranulomatosis, Henoch-Sch6nlein purpura, microscopic polyangiitis,acute glomerulonephritis, pyelonephritis (for example as a result of:urolithiasis, benign prostate hyperplasia, diabetes, malformations,abuse of analgesics, Crohn's disease), glomerulosclerosis,arteriolonecrose of the kidney, tubulointerstitial diseases,nephropathic disorders such as primary and congenital or aquired renaldisorder, Alport syndrome, nephritis, immunological kidney disorderssuch as kidney transplant rejection and immunocomplex-induced renaldisorders, nephropathy induced by toxic substances, nephropathy inducedby contrast agents, diabetic and non-diabetic nephropathy, renal cysts,nephrosclerosis, hypertensive nephrosclerosis and nephrotic syndromewhich can be characterized diagnostically, for example by abnormallyreduced creatinine and/or water excretion, abnormally elevated bloodconcentrations of urea, nitrogen, potassium and/or creatinine, alteredactivity of renal enzymes, for example glutamyl synthetase, alteredurine osmolarity or urine volume, elevated microalbuminuria,macroalbuminuria, lesions on glomerulae and arterioles, tubulardilatation, hyperphosphataemia and/or the need for dialysis. The presentinvention also comprises the use of the compounds according to theinvention for the treatment and/or prophylaxis of sequelae of renalinsufficiency, for example pulmonary oedema, heart failure, uremia,anemia, electrolyte disturbances (for example hypercalemia,hyponatremia) and disturbances in bone and carbohydrate metabolism.

The present invention also comprises the use of the compounds accordingto the invention for the treatment and/or prevention of sequelae ofrenal insufficiency, for example pulmonary oedema, heart failure,uraemia, anaemia, electrolyte disturbances (for example hyperkalaemia,hyponatraemia) and disturbances in bone and carbohydrate metabolism.

The compounds according to the invention are further suitable for thetreatment and/or prevention of polycystic kidney disease (PCKD) and ofthe syndrome of inappropriate ADH secretion (SIADH).

Furthermore, the compounds according to the invention are also suitablefor the treatment and/or prophylaxis of metabolic syndrome,hypertension, resistant hypertension, acute and chronic heart failure,coronary heart disease, stable and unstable angina pectoris, peripheraland cardiac vascular disorders, arrhythmias, atrial and ventriculararrhythmias and impaired conduction, for example atrioventricular blocksdegrees I-III (AB block I-III), supraventricular tachyarrhythmia, atrialfibrillation, atrial flutter, ventricular fibrillation, ventricularflutter, ventricular tachyarrhythmia, Torsade de pointes tachycardia,atrial and ventricular extrasystoles, AV-junctional extrasystoles, sicksinus syndrome, syncopes, AV-nodal re-entry tachycardia,Wolff-Parkinson-White syndrome, of acute coronary syndrome (ACS),autoimmune cardiac disorders (pericarditis, endocarditis, valvolitis,aortitis, cardiomyopathies), shock such as cardiogenic shock, septicshock and anaphylactic shock, aneurysms, boxer cardiomyopathy (prematureventricular contraction (PVC)), for treatment and/or prophylaxis ofthromboembolic disorders and ischaemias such as myocardial ischaemia,myocardial infarction, stroke, cardiac hypertrophy, transient andischaemic attacks, preeclampsia, inflammatory cardiovascular disorders,spasms of the coronary arteries and peripheral arteries, oedemaformation, for example pulmonary oedema, cerebral oedema, renal oedemaor oedema caused by heart failure, peripheral circulatory disturbances,reperfusion damage, arterial and venous thromboses, myocardialinsufficiency, endothelial dysfunction, to prevent restenoses, forexample after thrombolysis therapies, percutaneous transluminalangioplasties (PTA), transluminal coronary angioplasties (PTCA), hearttransplants and bypass operations, and also micro- and macrovasculardamage (vasculitis), increased levels of fibrinogen and of low-densitylipoprotein (LDL) and increased concentrations of plasminogen activatorinhibitor 1 (PAI-1), and also for treatment and/or prophylaxis oferectile dysfunction and female sexual dysfunction.

In addition, the compounds according to the invention are also suitablefor treatment and/or prophylaxis of asthmatic disorders, pulmonaryarterial hypertension (PAH) and other forms of pulmonary hypertension(PH) including left-heart disease, HIV, sickle cell anaemia,thromboembolisms (CTEPH), sarcoidosis, COPD or pulmonaryfibrosis-associated pulmonary hypertension, chronic-obstructivepulmonary disease (COPD), acute respiratory distress syndrome (ARDS),acute lung injury (ALI), alpha-1-antitrypsin deficiency (AATD),pulmonary fibrosis, pulmonary emphysema (for example pulmonary emphysemainduced by cigarette smoke) and cystic fibrosis (CF).

The compounds described in the present invention are also activecompounds for control of central nervous system disorders characterizedby disturbances of the NO/cGMP system. They are suitable in particularfor improving perception, concentration, learning or memory aftercognitive impairments like those occurring in particular in associationwith situations/diseases/syndromes such as mild cognitive impairment,age-associated learning and memory impairments, age-associated memorylosses, vascular dementia, craniocerebral trauma, stroke, dementiaoccurring after strokes (post stroke dementia), post-traumaticcraniocerebral trauma, general concentration impairments, concentrationimpairments in children with learning and memory problems, Alzheimer'sdisease, Lewy body dementia, dementia with degeneration of the frontallobes including Pick's syndrome, Parkinson's disease, progressivedementia with corticobasal degeneration, amyolateral sclerosis (ALS),Huntington's disease, demyelinization, multiple sclerosis, thalamicdegeneration, Creutzfeld-Jacob dementia, HIV dementia, schizophreniawith dementia or Korsakoff's psychosis. They are also suitable fortreatment and/or prophylaxis of central nervous system disorders such asstates of anxiety, tension and depression, CNS-related sexualdysfunctions and sleep disturbances, and for controlling pathologicaldisturbances of the intake of food, stimulants and addictive substances.

The compounds according to the invention are furthermore also suitablefor controlling cerebral blood flow and thus represent effective agentsfor controlling migraines. They are also suitable for the prophylaxisand control of sequelae of cerebral infarction (cerebral apoplexy) suchas stroke, cerebral ischaemia and craniocerebral trauma. The compoundsaccording to the invention can likewise be used for controlling statesof pain and tinnitus.

In addition, the compounds according to the invention haveanti-inflammatory action and can therefore be used as anti-inflammatoryagents for treatment and/or prophylaxis of sepsis (SIRS), multiple organfailure (MODS, MOF), inflammatory disorders of the kidney, chronicintestinal inflammations (IBD, Crohn's disease, UC), pancreatitis,peritonitis, rheumatoid disorders, inflammatory skin disorders andinflammatory eye disorders.

Furthermore, the compounds according to the invention can also be usedfor treatment and/or prophylaxis of autoimmune diseases.

The compounds according to the invention are also suitable for treatmentand/or prophylaxis of fibrotic disorders of the internal organs, forexample the lung, the heart, the kidney, the bone marrow and inparticular the liver, and also dermatological fibroses and fibrotic eyedisorders. In the context of the present invention, the term fibroticdisorders includes in particular the following terms: hepatic fibrosis,cirrhosis of the liver, pulmonary fibrosis, endomyocardial fibrosis,nephropathy, glomerulonephritis, interstitial renal fibrosis, fibroticdamage resulting from diabetes, bone marrow fibrosis and similarfibrotic disorders, scleroderma, morphea, keloids, hypertrophic scarring(also following surgical procedures), naevi, diabetic retinopathy,proliferative vitroretinopathy and disorders of the connective tissue(for example sarcoidosis).

The compounds according to the invention are also suitable forcontrolling postoperative scarring, for example as a result of glaucomaoperations.

The compounds according to the invention can also be used cosmeticallyfor ageing and keratinized skin.

Moreover, the compounds according to the invention are suitable fortreatment and/or prophylaxis of hepatitis, neoplasms, osteoporosis,glaucoma and gastroparesis.

The present invention further provides for the use of the compoundsaccording to the invention for treatment and/or prophylaxis ofdisorders, especially the disorders mentioned above.

The present invention further provides for the use of the compoundsaccording to the invention for the treatment and/or prophylaxis ofchronic renal disorders, acute and chronic renal insufficiency,diabetic, inflammatory or hypertensive nephropaties, fibrotic disorders,cardiac insufficiency, angina pectoris, hypertension, pulmonaryhypertension, ischemias, vascular disorders, thromboembolic disorders,arteriosclerosis, sickle cell anemia, erectile dysfunction, benignprostate hyperplasia, dysuria associated with benign prostatehyperplasia, Huntington, dementia, Alzheimer and Creutzfeld-Jakob.

The present invention further provides a method for treatment and/orprophylaxis of disorders, in particular the disorders mentioned above,using an effective amount of at least one of the compounds according tothe invention.

The present invention further provides a method for the treatment and/orprophylaxis of chronic renal disorders, acute and chronic renalinsufficiency, diabetic, inflammatory or hypertensive nephropathies,fibrotic disorders, cardiac insufficiency, angina pectoris,hypertension, pulmonary hypertension, ischemias, vascular disorders,thromboembolic disorders, arteriosclerosis, sickle cell anemia, erectiledysfunction, benign prostate hyperplasia, dysuria associated with benignprostate hyperplasia, Huntington, dementia, Alzheimer andCreutzfeld-Jakob.

In another embodiment, the inventive compounds can also be used to treator to prevent uterine fibroids (uterine leiomyoma or uterine myoma) inwomen.

Uterine fibroids are benign tumors of the myometrium, the smooth musclelayer of the uterus. Uterine fibroids grow slowly during a women's life,and their growth is dependent on the female sexual hormones estradioland progesterone [Kawaguchi K et al. Immunohistochemical analysis ofoestrogen receptors, progesterone receptors and Ki-67 in leiomyoma andmyometrium during the menstrual cycle and pregnancy Virchows Arch APathol Anat Histopathol. 1991; 419(4):309-15.], therefore the highestprevalence of uterine fibroids with approx. 70% and >80% in white andafro-american women, respectively, is found from 35 years of age onwardsto menopause, when they shrink due to reduced hormone levels [Baird D Det al. High cumulative incidence of uterine leiomyoma in black and whitewomen: Ultrasound evidence Am J Obstet Gynecol. 2003 January;188(1):100-7.]. Approx 30% and 45% of white and afro-american women,respectively, do show clinically relevant symptoms due to theirfibroids, which are heavy menstrual bleeding and pain, which is relatedto the menstrual cycle [David M et al. Myoma-associated pain frequencyand intensity: a retrospective evaluation of 1548 myoma patients. Eur JObstet Gynecol Reprod Biol. 2016 April; 199:137-40]. Heavy menstrualbleeding in this respect is defined by a blood loss of more than 80 mLin a menstrual bleeding period [Fraser I S et al. The FIGORecommendations on Terminologies and Definitions for Normal and AbnormalUterine Bleeding, Semin Reprod Med 2011; 29(5): 383-390]. Submucosalposition of the uterine fibroids, e.g. those located directly below theendometrium, seems to have an even more severe effect on uterinebleeding, which may result in anemia in affected women [Yang J H et al.Impact of submucous myoma on the severity of anemia. Fertil Steril. 2011April; 95(5):1769-72]. Furthermore, uterine fibroids, due to theirsymptoms, do severly affect the quality of life of affected women[Downes E et al. The burden of uterine fibroids in five Europeancountries. Eur J Obstet Gynecol Reprod Biol. 2010 September;152(1):96-102].

So far, it is not understood how uterine fibroids do cause heavymenstrual bleeding. Disregulated genes in uterine fibroids, incomparison to normal myometrium, can give a hint to understand theunderlying mechanisms. In published and internal studies, we found TDO2,Tryptophan 2,3-dioxygenase, being highly upregulated [Tsibris J C et al.Insights from gene arrays on the development and growth regulation ofuterine leiomyomata. Fertil Steril. 2002 July; 78(1):114-21.]. TDO2metabolizes the substrate L-Tryptophan to L-Kynurenine, which can befurther metabolized to kynurenic acid. Both, L-Kynurenine and Kynurenicacid are physiological ligands and activators for the arylhydrocarbonreceptor AHR [Opitz C A et al. An endogenous tumour-promoting ligand ofthe human aryl hydrocarbon receptor Nature. 2011 Oct. 5;478(7368):197-203].

L-Kynurenine controls at least two physiological processes which aredysregulated in uterine fibroids. L-Kynurenine, synthesized by anupregulation of IDO (Indoleamine-2,3-dyoxygenase) or TDO2, and actingvia the AHR receptor, suppresses the immune system and thus preventsimmune cells from recognizing and clearing the tumor cells [Munn D HBlocking IDO activity to enhance anti-tumor immunity. Front Biosci(Elite Ed). 2012 Jan. 1; 4:734-45]. Furthermore, an upregulation ofL-Kynurenine leads to a vasodilation of vessels, and thus can directlyincrease blood loss and bleeding [Wang Y et al. Kynurenine is anendothelium-derived relaxing factor produced during inflammation NatureMedicine 16, 279-285 (2010)].

In summary, the upregulation of L-Kynurenine through activation of itsphysiological receptor AHR seems to support uterine fibroid growth bylocal suppression of the immune system, and might cause heavy menstrualbleeding by vasodilation of endometrial vessels in proximity to thetumor.

Therefore, a systemic or local application of compounds from the presentinvention inhibiting activation of the AHR and thus blocking the effectof uterine fibroid derived L-Kynurenine presents a new and validtreatment option for uterine fibroids.

Compounds of the present invention can be utilized to inhibit, block,reduce or decrease AHR activation by exogenous and/or endogenous ligandsfor the reduction of tumour growth and the modulation of dysregulatedimmune responses e.g. to block immunosuppression and increase immunecell activation and infiltration in the context of cancer and cancerimmunotherapy; This method comprises administering to a mammal in needthereof, including a human, an amount of a compound of this invention,or a pharmaceutically acceptable salt, isomer, polymorph, metabolite,hydrate, solvate or ester thereof; which is effective to treat thedisorder.

The present invention also provides methods of treating a variety ofother disorders wherein AHR is involved such as, but not limited to,inflammation, vaccination for infection & cancer, viral infections,obesity and diet-induced obesity, adiposity, metabolic disorders,hepatic steatosis and uterine fibroids.

These disorders have been well characterized in humans, but also existwith a similar etiology in other mammals, and can be treated byadministering pharmaceutical compositions of the present invention.

The term “treating” or “treatment” as used in the present text is usedconventionally, e.g., the management or care of a subject for thepurpose of combating, alleviating, reducing, relieving, improving thecondition of a disease or disorder, such as liquid and solid tumours.

In accordance with a further aspect, the present invention coverscompounds of general formula (I), as described supra, or stereoisomers,tautomers, N-oxides, hydrates, solvates, and salts thereof, particularlypharmaceutically acceptable salts thereof, or mixtures of same, for usein the treatment or prophylaxis of diseases, in particular cancer orconditions with dysregulated immune responses or other disordersassociated with aberrant AHR signaling.

The pharmaceutical activity of the compounds according to the inventioncan be explained by their activity as AHR inhibitors.

In accordance with a further aspect, the present invention covers theuse of compounds of general formula (I), as described supra, orstereoisomers, tautomers, N-oxides, hydrates, solvates, and saltsthereof, particularly pharmaceutically acceptable salts thereof, ormixtures of same, for the treatment or prophylaxis of diseases, inparticular cancer or conditions with dysregulated immune responses orother disorders associated with aberrant AHR signaling, particularlyliquid and solid tumours.

In accordance with a further aspect, the present invention covers theuse of a compound of formula (I), described supra, or a stereoisomer, atautomer, an N-oxide, a hydrate, a solvate, or a salt thereof,particularly a pharmaceutically acceptable salt thereof, or a mixture ofsame, for the prophylaxis or treatment of diseases, in particular canceror conditions with dysregulated immune responses or other disordersassociated with aberrant AHR signaling, particularly liquid and solidtumours.

In accordance with a further aspect, the present invention covers theuse of compounds of general formula (I), as described supra, orstereoisomers, tautomers, N-oxides, hydrates, solvates, and saltsthereof, particularly pharmaceutically acceptable salts thereof, ormixtures of same, in a method of treatment or prophylaxis of diseases,in particular cancer or conditions with dysregulated immune responses orother disorders associated with aberrant AHR signaling, particularlyliquid and solid tumours.

In accordance with a further aspect, the present invention covers use ofa compound of general formula (I), as described supra, or stereoisomers,tautomers, N-oxides, hydrates, solvates, and salts thereof, particularlypharmaceutically acceptable salts thereof, or mixtures of same, for thepreparation of a pharmaceutical composition, preferably a medicament,for the prophylaxis or treatment of diseases, in particular cancer orconditions with dysregulated immune responses or other disordersassociated with aberrant AHR signaling, particularly liquid and solidtumours.

In accordance with a further aspect, the present invention covers amethod of treatment or prophylaxis of diseases, in particular cancer orconditions with dysregulated immune responses or other disordersassociated with aberrant AHR signaling, particularly liquid and solidtumours, using an effective amount of a compound of general formula (I),as described supra, or stereoisomers, tautomers, N-oxides, hydrates,solvates, and salts thereof, particularly pharmaceutically acceptablesalts thereof, or mixtures of same.

In accordance with a further aspect, the present invention coverspharmaceutical compositions, in particular a medicament, comprising acompound of general formula (I), as described supra, or a stereoisomer,a tautomer, an N-oxide, a hydrate, a solvate, a salt thereof,particularly a pharmaceutically acceptable salt, or a mixture of same,and one or more excipients), in particular one or more pharmaceuticallyacceptable excipient(s). Conventional procedures for preparing suchpharmaceutical compositions in appropriate dosage forms can be utilized.

The present invention furthermore covers pharmaceutical compositions, inparticular medicaments, which comprise at least one compound accordingto the invention, conventionally together with one or morepharmaceutically suitable excipients, and to their use for the abovementioned purposes.

It is possible for the compounds according to the invention to havesystemic and/or local activity. For this purpose, they can beadministered in a suitable manner, such as, for example, via the oral,parenteral, pulmonary, nasal, sublingual, lingual, buccal, rectal,vaginal, dermal, transdermal, conjunctival, otic route or as an implantor stent.

For these administration routes, it is possible for the compoundsaccording to the invention to be administered in suitable administrationforms.

For oral administration, it is possible to formulate the compoundsaccording to the invention to dosage forms known in the art that deliverthe compounds of the invention rapidly and/or in a modified manner, suchas, for example, tablets (uncoated or coated tablets, for example withenteric or controlled release coatings that dissolve with a delay or areinsoluble), orally-disintegrating tablets, films/wafers,films/lyophylisates, capsules (for example hard or soft gelatinecapsules), sugar-coated tablets, granules, pellets, powders, emulsions,suspensions, aerosols or solutions. It is possible to incorporate thecompounds according to the invention in crystalline and/or amorphisedand/or dissolved form into said dosage forms.

Parenteral administration can be effected with avoidance of anabsorption step (for example intravenous, intraarterial, intracardial,intraspinal or intralumbal) or with inclusion of absorption (for exampleintramuscular, subcutaneous, intracutaneous, percutaneous orintraperitoneal). Administration forms which are suitable for parenteraladministration are, inter alia, preparations for injection and infusionin the form of solutions, suspensions, emulsions, lyophylisates orsterile powders.

Examples which are suitable for other administration routes arepharmaceutical forms for inhalation [inter alia powder inhalers,nebulizers], nasal drops, nasal solutions, nasal sprays;tablets/films/wafers/capsules for lingual, sublingual or buccaladministration; suppositories; eye drops, eye ointments, eye baths,ocular inserts, ear drops, ear sprays, ear powders, ear-rinses, eartampons; vaginal capsules, aqueous suspensions (lotions, mixturaeagitandae), lipophilic suspensions, emulsions, ointments, creams,transdermal therapeutic systems (such as, for example, patches), milk,pastes, foams, dusting powders, implants or stents.

The compounds according to the invention can be incorporated into thestated administration forms. This can be effected in a manner known perse by mixing with pharmaceutically suitable excipients. Pharmaceuticallysuitable excipients include, inter alia,

fillers and carriers (for example cellulose, microcrystalline cellulose(such as, for example, Avicel®), lactose, mannitol, starch, calciumphosphate (such as, for example, Di-Cafos®)),ointment bases (for example petroleum jelly, paraffins, triglycerides,waxes, wool wax, wool wax alcohols, lanolin, hydrophilic ointment,polyethylene glycols),bases for suppositories (for example polyethylene glycols, cacao butter,hard fat),solvents (for example water, ethanol, isopropanol, glycerol, propyleneglycol, medium chain-length triglycerides fatty oils, liquidpolyethylene glycols, paraffins),surfactants, emulsifiers, dispersants or wetters (for example sodiumdodecyl sulfate), lecithin, phospholipids, fatty alcohols (such as, forexample, Lanette®), sorbitan fatty acid esters (such as, for example,Span®), polyoxyethylene sorbitan fatty acid esters (such as, forexample, Tween®), polyoxyethylene fatty acid glycerides (such as, forexample, Cremophor®), polyoxethylene fatty acid esters, polyoxyethylenefatty alcohol ethers, glycerol fatty acid esters, poloxamers (such as,for example, Pluronic®),buffers, acids and bases (for example phosphates, carbonates, citricacid, acetic acid, hydrochloric acid, sodium hydroxide solution,ammonium carbonate, trometamol, triethanolamine),isotonicity agents (for example glucose, sodium chloride),adsorbents (for example highly-disperse silicas),viscosity-increasing agents, gel formers, thickeners and/or binders (forexample polyvinylpyrrolidone, methylcellulose,hydroxypropylmethylcellulose, hydroxypropylcellulose,carboxymethylcellulose-sodium, starch, carbomers, polyacrylic acids(such as, for example, Carbopol®); alginates, gelatine),disintegrants (for example modified starch,carboxymethylcellulose-sodium, sodium starch glycolate (such as, forexample, Explotab®), cross-linked polyvinylpyrrolidone,croscarmellose-sodium (such as, for example, AcDiSol®)),flow regulators, lubricants, glidants and mould release agents (forexample magnesium stearate, stearic acid, talc, highly-disperse silicas(such as, for example, Aerosil®)),coating materials (for example sugar, shellac) and film formers forfilms or diffusion membranes which dissolve rapidly or in a modifiedmanner (for example polyvinylpyrrolidones (such as, for example,Kollidon®), polyvinyl alcohol, hydroxypropylmethylcellulose,hydroxypropylcellulose, ethylcellulose, hydroxypropylmethylcellulosephthalate, cellulose acetate, cellulose acetate phthalate,polyacrylates, polymethacrylates such as, for example, Eudragit®)),capsule materials (for example gelatine, hydroxypropylmethylcellulose),synthetic polymers (for example polylactides, polyglycolides,polyacrylates, polymethacrylates (such as, for example, Eudragit®),polyvinylpyrrolidones (such as, for example, Kollidon®), polyvinylalcohols, polyvinyl acetates, polyethylene oxides, polyethylene glycolsand their copolymers and blockcopolymers),plasticizers (for example polyethylene glycols, propylene glycol,glycerol, triacetine, triacetyl citrate, dibutyl phthalate),penetration enhancers,stabilisers (for example antioxidants such as, for example, ascorbicacid, ascorbyl palmitate, sodium ascorbate, butylhydroxyanisole,butylhydroxytoluene, propyl gallate),preservatives (for example parabens, sorbic acid, thiomersal,benzalkonium chloride, chlorhexidine acetate, sodium benzoate),colourants (for example inorganic pigments such as, for example, ironoxides, titanium dioxide),flavourings, sweeteners, flavour- and/or odour-masking agents.

The present invention furthermore relates to a pharmaceuticalcomposition which comprise at least one compound according to theinvention, conventionally together with one or more pharmaceuticallysuitable excipient(s), and to their use according to the presentinvention.

In accordance with another aspect, the present invention coverspharmaceutical combinations, in particular medicaments, comprising atleast one compound of general formula (I) of the present invention andat least one or more further active ingredients, in particular for thetreatment and/or prophylaxis of cancer or conditions with dysregulatedimmune responses or other disorders associated with aberrant AHRsignalinggeneric name disorders, particularly liquid and solid tumours.

The term “combination” in the present invention is used as known topersons skilled in the art, it being possible for said combination to bea fixed combination, a non-fixed combination or a kit-of-parts.

A “fixed combination” in the present invention is used as known topersons skilled in the art and is defined as a combination wherein, forexample, a first active ingredient, such as one or more compounds ofgeneral formula (I) of the present invention, and a further activeingredient are present together in one unit dosage or in one singleentity. One example of a “fixed combination” is a pharmaceuticalcomposition wherein a first active ingredient and a further activeingredient are present in admixture for simultaneous administration,such as in a formulation. Another example of a “fixed combination” is apharmaceutical combination wherein a first active ingredient and afurther active ingredient are present in one unit without being inadmixture.

A non-fixed combination or “kit-of-parts” in the present invention isused as known to persons skilled in the art and is defined as acombination wherein a first active ingredient and a further activeingredient are present in more than one unit. One example of a non-fixedcombination or kit-of-parts is a combination wherein the first activeingredient and the further active ingredient are present separately. Itis possible for the components of the non-fixed combination orkit-of-parts to be administered separately, sequentially,simultaneously, concurrently or chronologically staggered.

Based upon standard laboratory techniques known to evaluate compoundsuseful for the treatment of cancer or conditions with dysregulatedimmune responses or other disorders associated with aberrant AHRsignaling, by standard toxicity tests and by standard pharmacologicalassays for the determination of treatment of the conditions identifiedabove in mammals, and by comparison of these results with the results ofknown active ingredients or medicaments that are used to treat theseconditions, the effective dosage of the compounds of the presentinvention can readily be determined for treatment of each desiredindication. The amount of the active ingredient to be administered inthe treatment of one of these conditions can vary widely according tosuch considerations as the particular compound and dosage unit employed,the mode of administration, the period of treatment, the age and sex ofthe patient treated, and the nature and extent of the condition treated.

The total amount of the active ingredient to be administered willgenerally range from about 0.001 mg/kg to about 200 mg/kg body weightper day, and preferably from about 0.01 mg/kg to about 20 mg/kg bodyweight per day. Clinically useful dosing schedules will range from oneto three times a day dosing to once every four weeks dosing. Inaddition, it is possible for “drug holidays”, in which a patient is notdosed with a drug for a certain period of time, to be beneficial to theoverall balance between pharmacological effect and tolerability. It ispossible for a unit dosage to contain from about 0.5 mg to about 1500 mgof active ingredient, and can be administered one or more times per dayor less than once a day. The average daily dosage for administration byinjection, including intravenous, intramuscular, subcutaneous andparenteral injections, and use of infusion techniques will preferably befrom 0.01 to 200 mg/kg of total body weight. The average daily rectaldosage regimen will preferably be from 0.01 to 200 mg/kg of total bodyweight. The average daily vaginal dosage regimen will preferably be from0.01 to 200 mg/kg of total body weight. The average daily topical dosageregimen will preferably be from 0.1 to 200 mg administered between oneto four times daily. The transdermal concentration will preferably bethat required to maintain a daily dose of from 0.01 to 200 mg/kg. Theaverage daily inhalation dosage regimen will preferably be from 0.01 to100 mg/kg of total body weight.

Of course the specific initial and continuing dosage regimen for eachpatient will vary according to the nature and severity of the conditionas determined by the attending diagnostician, the activity of thespecific compound employed, the age and general condition of thepatient, time of administration, route of administration, rate ofexcretion of the drug, drug combinations, and the like. The desired modeof treatment and number of doses of a compound of the present inventionor a pharmaceutically acceptable salt or ester or composition thereofcan be ascertained by those skilled in the art using conventionaltreatment tests.

EXPERIMENTAL SECTION

NMR peak forms are stated as they appear in the spectra, possible higherorder effects have not been considered. The multiplicities are statedaccording to the signal form which appears in the spectrum,NMR-spectroscopic effects of a higher order were not taken intoconsideration. Multiplicity of the NMR signals: s=singlet, d=doublet,t=triplet, q=quartet, qi, quin=quintet, b, br=broad signal, m=multiplet.NMR signals: shift in ppm. Combinations of multiplicity could be e.g.dd=doublet from doublet.

Chemical names were generated using the ACD/Name software from ACD/Labs.In some cases generally accepted names of commercially availablereagents were used in place of ACD/Name generated names.

Table 1 lists the abbreviations used in this paragraph and in theExamples section as far as they are not explained within the text body.Other abbreviations have their meanings customary per se to the skilledperson.

TABLE 1 Abbreviations ACN acetonitrile AcOH acetic acid BPR BackPressure Regulator CDCl₃ deuterochloroform DAD diode array detector DCMdichloromethane DEA diethylamine DIPEA N,N-Diisopropylethylamine DMAN,N-dimethylacetamide DME 1,2-dimethoxyethane DMF N,N-dimethylformamideDMSO-d6 deuterated dimethyl sulfoxide DMSO dimethyl sulfoxide EtOAcethyl acetate Eq equivalent ESI electrospray ionisation Expl. exampleHATU (7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluroniumhexafluorophosphate HBTU O-benzotriazole-N,N,N′,N′-tetramethyluroniumhexafluorophosphate HPLC high-pressure liquid chromatography KAkynurenic acid LCMS liquid chromatography coupled with mass spectrometryLPS lipopolysaccharide mL milliliter min. minute(s) M molar MS massspectrometry MTBE methyl tert-butyl ether NMP N-Methyl-2-pyrrolidone ppressure PBMC peripheral blood mononuclear cells PyBOB(benzotriazol-1-yl)oxytripyrrolidinophosphonium hexafluorophosphateRP-HPLC reverse-phase high-pressure liquid chromatography Rt retentiontime rt, r.t. room temperature sat. saturated T3P2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphorinane 2,4,6-trioxide TEAtriethylamine THF tetrahydrofuran TFA trifluoroacetic acid TLC thinlayer chromatography TNFa tumour necrosis factor alpha μM micromolarUPLC Ultra high performance chromatography Xphos2-Dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl

The various aspects of the invention described in this application areillustrated by the following examples which are not meant to limit theinvention in any way.

The example testing experiments described herein serve to illustrate thepresent invention and the invention is not limited to the examplesgiven.

EXPERIMENTAL SECTION—GENERAL PART

All reagents, for which the synthesis is not described in theexperimental part, are either commercially available, or are knowncompounds or may be formed from known compounds by known methods by aperson skilled in the art.

The compounds and intermediates produced according to the methods of theinvention may require purification. Purification of organic compounds iswell known to the person skilled in the art and there may be severalways of purifying the same compound. In some cases, no purification maybe necessary. In some cases, the compounds may be purified bycrystallization. In some cases, impurities may be stirred out using asuitable solvent. In some cases, the compounds may be purified bychromatography, particularly flash column chromatography, using forexample prepacked silica gel cartridges, e.g. Biotage SNAP cartidgesKP-Sil® or KP-NH® in combination with a Biotage autopurifier system(SP4® or Isolera Four®) and eluents such as gradients of hexane/ethylacetate or DCM/methanol. In some cases, the compounds may be purified bypreparative HPLC using for example a Waters autopurifier equipped with adiode array detector and/or on-line electrospray ionization massspectrometer in combination with a suitable prepacked reverse phasecolumn and eluents such as gradients of water and acetonitrile which maycontain additives such as trifluoroacetic acid, formic acid or aqueousammonia.

In some cases, purification methods as described above can provide thosecompounds of the present invention which possess a sufficiently basic oracidic functionality in the form of a salt, such as, in the case of acompound of the present invention which is sufficiently basic, atrifluoroacetate or formate salt for example, or, in the case of acompound of the present invention which is sufficiently acidic, anammonium salt for example. A salt of this type can either be transformedinto its free base or free acid form, respectively, by various methodsknown to the person skilled in the art, or be used as salts insubsequent biological assays. It is to be understood that the specificform (e.g. salt, free base etc.) of a compound of the present inventionas isolated and as described herein is not necessarily the only form inwhich said compound can be applied to a biological assay in order toquantify the specific biological activity.

UPLC/MS-Methods Method 1:

Instrument: Waters Acquity UPLCMS SingleQuad; Column: Acquity UPLC BEHC18 1.7 μm, 50×2.1 mm; eluent A: water+0.2 vol % aqueous ammonia (32%),eluent B: acetonitrile; gradient: 0-1.6 min 1-99% B, 1.6-2.0 min 99% B;flow 0.8 ml/min; temperature: 60° C.; DAD scan: 210-400 nm.

Method 2:

Instrument: Waters Acquity UPLCMS SingleQuad; Column: Acquity UPLC BEHC18 1.7 μm, 50×2.1 mm; eluent A: water+0.1 vol % formic acid (99%),eluent B: acetonitrile; gradient: 0-1.6 min 1-99% B, 1.6-2.0 min 99% B;flow 0.8 ml/min; temperature: 60° C.; DAD scan: 210-400 nm.

Method 3:

Instrument: Waters Autopurification MS SingleQuad; Column: WatersXBrigde C18 5p 100×30 mm; eluent A: water+0.2 vol % aqueous ammonia(32%), eluent B: acetonitrile; gradient: 0-5.5 min 5-100% B; flow 70ml/min; temperature: 25° C.; DAD scan: 210-400 nm.

EXPERIMENTAL SECTION—INTERMEDIATES Intermediate 12-Chloro-6-[4-(trifluoromethoxy)phenyl]pyrimidine-4-carboxylic acid

Methyl 2,6-dichloropyrimidine-4-carboxylate (1.00 g, 4.83 mmol) and[4-(trifluoromethoxy)phenyl]boronic acid (895 mg, 4.35 mmol) weredissolved in 20 mL dioxane, sodium carbonate (7.2 mL, 2.0 M, 14 mmol)and tetrakis(triphenylphosphine)palladium(0) (558 mg, 483 μmol) wereadded. The mixture was stirred for 2 h at 90° C. The reaction mixturewas filtered and the precipitate was washed with DCM to give the titlecompound as a salt (2.47 g, 4.65 mmol, 60% purity).

LC-MS (Method 1): Rt=0.71 min; MS (ESIpos): m/z=319 [M+H]⁺

1H-NMR (400 MHz, DMSO-d6): δ [ppm]=7.57 (dd, 2H), 8.35-8.44 (m, 2H),8.54 (s, 1H)

Intermediate 22,6-Dichloro-N-[(2S)-1-hydroxypropan-2-yl]pyrimidine-4-carboxamide

2,6-Dichloropyrimidine-4-carboxylic acid (1.00 g, 5.18 mmol) wassolubilised in 8 mL DMF, (2S)-2-aminopropan-1-ol (810 μL, 10 mmol),N,N-diisopropylethylamine (5.4 mL, 31 mmol) and T3P solution (9 mL, 50%in DMF, 16 mmol) were added and it was stirred for 2 h at rt. Thereaction was diluted with water and extracted twice with DCM. Theorganic layer was dried over a silicone filter and concentrated underreduced pressure to obtain the title compound (1.9 g, 2.70 mmol, 75%purity).

LC-MS (Method 1): Rt=0.79 min; MS (ESIneg): m/z=248 [M−H]⁻

¹H-NMR (400 MHz, DMSO-d₆): 6 [ppm]=1.14 (d, 3H), 3.39-3.50 (m, 2H),3.98-4.07 (m, 1H), 5.76 (s, 1H), 7.90-8.00 (m, 1H), 8.11 (s, 1H)

Intermediate 32-Chloro-N-[(2S)-1-hydroxypropan-2-yl]-6-[4-(trifluoromethoxy)phenyl]pyrimidine-4-carboxamide

2,6-Dichloro-N-[(2S)-1-hydroxypropan-2-yl]pyrimidine-4-carboxamide (1.93g, 45% purity, 3.47 mmol) and [4-(trifluoromethoxy)phenyl]boronic acid(643 mg, 3.12 mmol) were dissolved in a mixture of 15 mL dioxane and 2.9mL water, aqueous potassium carbonate solution (5.2 mL, 2.0 M, 10 mmol)andBis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II)(244 mg, 347 μmol) were added. The mixture was stirred for 2 h at 80° C.The reaction was concentrated under reduced pressure. The residue waspurified using a 25 g Ultra Sil-cartridge, 100% Hex-80% EtOAc, to giveof the title compound 117 mg (75% purity, 7% yield) and 240 mg (94%purity, 17% yield).

LC-MS (Method 1): Rt=1.25 min; MS (ESIneg): m/z=374 [M−H]⁻

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=1.18 (d, 3H), 3.41-3.56 (m, 2H),3.99-4.06 (m, 1H), 4.88 (t, 1H), 7.57 (dd, 2H), 8.39-8.45 (m, 2H), 8.52(s, 1H), 8.59 (d, 1H)

Intermediate 42-Chloro-N-[(2R)-1-hydroxypropan-2-yl]-6-[4-(trifluoromethoxy)phenyl]pyrimidine-4-carboxamide

2-Chloro-6-[4-(trifluoromethoxy)phenyl]pyrimidine-4-carboxylic acid(1.20 g, 88% purity, 3.31 mmol), (2R)-2-aminopropan-1-ol (390 μL, 5.0mmol), sodium bicarbonate (1.67 g, 19.9 mmol) and HATU (3.78 g, 9.94mmol) were stirred in 17 mL DMF overnight at rt. The mixture was dilutedwith EtOAc and washed with half saturated brine thrice. The organicphase was dried over a silicone filter and concentrated under reducedpressure The residue was purified using a 50 g Ultra Sil-cartridge, 100%Hex-100% EtOAc, to give 312 mg (63% purity, 16% yield) of the titlecompound.

LC-MS (Method 1): Rt=1.25 min; MS (ESIpos): m/z=376 [M+H]⁺

Intermediate 52-Chloro-N-(2-hydroxy-2-methylpropyl)-6-[4-(trifluoromethoxy)phenyl]pyrimidine-4-carboxamide

2-Chloro-6-[4-(trifluoromethoxy)phenyl]pyrimidine-4-carboxylic acid(2.20 g, 60% purity, 4.14 mmol), 1-amino-2-methylpropan-2-ol (554 mg,6.21 mmol), N,N-diisopropylethylamine (3.6 mL, 21 mmol) and T3P solution(7.4 mL, 50% in DMF, 12 mmol) were stirred in 960 μL NMP for 1 h at rt.The reaction was diluted with water and stirred for 30 min. The aqueousmixture was extracted with DCM. The organic layer was washed with halfsaturated brine thrice, dried over a silicone filter and concentratedunder reduced pressure to give 2.0 g (4.11 mmol, 80% purity) of thetitle compound.

LC-MS (Method 1): Rt=1.31 min; MS (ESIpos): m/z=390 [M+H]⁺

Intermediate 62-Chloro-6-(3-fluorophenyl)-N-[(2S)-1-hydroxypropan-2-yl]pyrimidine-4-carboxamide

2,6-Dichloro-N-[(2S)-1-hydroxypropan-2-yl]pyrimidine-4-carboxamide (814mg, 3.25 mmol) and (3-fluorophenyl)boronic acid (410 mg, 2.93 mmol) weredissolved in a mixture of 13 mL dioxane and 2.7 mL water, aqueouspotassium carbonate solution (4.9 ml, 2.0 M, 9.8 mmol) andBis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II)(229 mg, 325 μmol) were added. The mixture was stirred for 2 h at 80° C.The reaction was diluted with water and the aqueous mixture wasextracted twice with DCM. The organic layer was dried over a siliconefilter and concentrated under reduced pressure to give the titlecompound. It was used without further purification.

LC-MS (Method 2): Rt=1.08 min; MS (ESIpos): m/z=309 [M+H]⁺

Intermediate 72-Chloro-6-[4-(trifluoromethyl)phenyl]pyrimidine-4-carboxylic acid

Methyl 2,6-dichloropyrimidine-4-carboxylate (150 mg, 725 μmol) and[4-(trifluoromethyl)phenyl]boronic acid (124 mg, 652 μmol) weredissolved in 3 mL dioxane, aqueous sodium carbonate solution (1.1 mL,2.0 M, 2.2 mmol) and tetrakis(triphenylphosphine)palladium(0) (83.7 mg,72.5 μmol) were added. The mixture was stirred for 2 h at 90° C. Thereaction mixture was filtered and the precipitate was washed with DCM togive the title compound as a salt (350 mg, 0.69 mmol, 60% purity).

LC-MS (Method 1): Rt=0.69 min; MS (ESIneg): m/z=301 [M−H]⁻

Intermediate 82-Chloro-N-(2-hydroxy-2-methylpropyl)-6-[4-(trifluoromethyl)phenyl]pyrimidine-4-carboxamide

2-Chloro-6-[4-(trifluoromethyl)phenyl]pyrimidine-4-carboxylic acid (1.70g, 60% purity, 3.37 mmol), 1-amino-2-methylpropan-2-ol (451 mg, 5.06mmol), N,N-diisopropylethylamine (2.9 mL, 17 mmol) and T3P solution (6.0mL, 50% in DMF, 10 mmol) were stirred in 960 μL NMP for 1 h at rt. Thereaction was diluted with water and stirred for 30 min. The aqueousmixture was extracted with DCM. The organic layer was washed with halfsaturated brine thrice, dried over a silicone filter and concentratedunder reduced pressure to give 740 mg (1.98 mmol, 57% purity) of thetitle compound.

LC-MS (Method 1): Rt=1.26 min; MS (ESIpos): m/z=374 [M+H]⁺

Intermediate 9 2-Chloro-6-(4-chlorophenyl)pyrimidine-4-carboxylic acid

Methyl 2,6-dichloropyrimidine-4-carboxylate (150 mg, 725 μmol) and(4-chlorophenyl)boronic acid (102 mg, 652 μmol) were dissolved in 3 mLdioxane, aqueous sodium carbonate solution (1.1 mL, 2.0 M, 2.2 mmol) andtetrakis(triphenylphosphine)palladium(0) (83.7 mg, 72.5 μmol) wereadded. The mixture was stirred for 2 h at 90° C. The reaction mixturewas filtered and the precipitate was washed with DCM to give the titlecompound as a salt (392 mg, 0.73 mmol, 50% purity).

LC-MS (Method 1): Rt=0.64 min; MS (ESIpos): m/z=268 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6): δ [ppm]=7.66 (d, 2H), 8.31 (d, 2H), 8.51 (s,1H), 13.95-14.75 (m, 1H)

Intermediate 102-Chloro-6-(4-chlorophenyl)-N-[(2S)-1-hydroxypropan-2-yl]pyrimidine-4-carboxamide

2-Chloro-6-(4-chlorophenyl)pyrimidine-4-carboxylic acid (500 mg, 1.86mmol), (2S)-2-aminopropan-1-ol (220 μL, 2.8 mmol), sodium bicarbonate(937 mg, 11.1 mmol) and HATU (2.12 g, 5.57 mmol) were stirred in 9.7 mLDMF overnight at rt. The mixture was concentrated under reducedpressure. The residue was purified using a 50 g Ultra Sil-cartridge,100% Hex-100% EtOAc, to give 197 mg (76% purity, 25% yield) of the titlecompound.

LC-MS (Method 1): Rt=1.19 min; MS (ESIpos): m/z=326 [M+H]⁺

1H-NMR (400 MHz, DMSO-d6): δ [ppm]=1.17 (d, 3H), 3.40-3.55 (m, 3H),4.01-4.12 (m, 1H), 4.89 (s, 1H), 7.66 (d, 3H), 8.28-8.33 (m, 3H), 8.51(s, 1H), 8.58 (d, 1H).

Intermediate 112-Chloro-6-(4-chlorophenyl)-N-[(2R)-1-hydroxypropan-2-yl]pyrimidine-4-carboxamide

2-Chloro-6-(4-chlorophenyl)pyrimidine-4-carboxylic acid (1.40 g, 55%purity, 2.86 mmol), (2R)-2-aminopropan-1-ol (330 μL, 4.3 mmol), sodiumbicarbonate (1.44 g, 17.2 mmol) and HATU (3.26 g, 8.58 mmol) werestirred in 15 mL DMF overnight at rt. The mixture was diluted with EtOAcand washed with half saturated brine thrice. The organic phase was driedover a silicone filter and concentrated under reduced pressure. Theresidue was purified using a 50 g Ultra Sil-cartridge, 100% Hex-100%EtOAc, to give 321 mg (50% purity, 17% yield) of the title compound.

LC-MS (Method 1): Rt=1.18 min; MS (ESIpos): m/z=326 [M+H]⁺

Intermediate 122-Chloro-6-(4-chlorophenyl)-N-(2-hydroxy-2-methylpropyl)pyrimidine-4-carboxamide

2-Chloro-6-(4-chlorophenyl)pyrimidine-4-carboxylic acid (2.0 g, 55%purity, 4.09 mmol), 1-amino-2-methylpropan-2-ol (0.55 mL, 6.13 mmol),N,N-diisopropylethylamine (3.56 mL, 20.44 mmol) and T3P solution (7.3mL, 50% in DMF, 12.3 mmol) were stirred in 10 mL NMP for 1 h at rt.Because of incomplete conversion stirring was continued overnight at rt.Again 1-amino-2-methylpropan-2-ol (0.55 mL, 6.13 mmol),N,N-diisopropylethylamine (3.56 mL, 20.44 mmol) and T3P solution (7.3mL, 50% in DMF, 12.3 mmol) were added and the mixture was stirred for 1h at rt. The reaction was diluted with water and stirred for 30 min. Theaqueous mixture was extracted with DCM. The organic layer was washedwith half saturated brine thrice, dried over a silicone filter andconcentrated under reduced pressure to give 2.3 g (4.06 mmol, 60%purity) of the title compound.

LC-MS (Method 1): Rt=1.24 min; MS (ESIpos): m/z=340 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6): δ [ppm]=1.13 (s, 6H), 3.31 (s, 2H), 4.75 (brs, 1H), 7.65-7.67 (m, 2H), 8.32 (d, 2H), 8.53 (s, 1H)

Intermediate 13 2,6-Bis(4-chlorophenyl)pyrimidine-4-carboxylic acid

Methyl 2,6-dichloropyrimidine-4-carboxylate (100 mg, 483 μmol) and(4-chlorophenyl)boronic acid (90.6 mg, 580 μmol) were dissolved in 2.0mL dioxane, aqueous sodium carbonate solution (720 μL, 2.0 M, 1.4 mmol)and tetrakis(triphenylphosphine)palladium(0) (55.8 mg, 48.3 μmol) wereadded. The mixture was stirred for 2 h at 90° C. The mixture wasconcentrated under reduced pressure. The residue was purified bypreparative HPLC to give 16.2 mg (95% purity, 9% yield) of the titlecompound.

LC-MS (Method 1): Rt=0.47 min; MS (ESIpos): m/z=345 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6): δ [ppm]=7.66 (d, 2H), 8.31 (d, 2H), 8.51 (s,1H), 13.95-14.75 (m, 1H) (OH proton is not visible.)

Intermediate 142,6-Bis[4-(trifluoromethoxy)phenyl]pyrimidine-4-carboxylic acid

Methyl 2,6-dichloropyrimidine-4-carboxylate (100 mg, 483 μmol) and[4-(trifluoromethoxy)phenyl]boronic acid (119 mg, 580 μmol) weredissolved in 2.0 mL dioxane, aqueous sodium carbonate solution (720 μL,2.0 M, 1.4 mmol) and tetrakis(triphenylphosphine)palladium(0) (55.8 mg,48.3 μmol) were added. The mixture was stirred for 4 h at 90° C. Themixture was concentrated under reduced pressure. The residue waspurified by preparative HPLC to give 9.90 mg (95% purity, 4% yield) ofthe title compound.

LC-MS (Method 1): Rt=1.53 min; MS (ESIpos): m/z=445 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6): δ [ppm]=7.54-7.62 (m, 4H), 8.45 (s, 1H),8.51-8.58 (m, 2H), 8.67 (d, 2H) (OH proton is not visible.

Intermediate 152-chloro-6-[4-(trifluoromethoxy)phenyl]pyrimidine-4-carboxylic acid

Methyl 2,6-dichloropyrimidine-4-carboxylate (5.00 g, 24.2 mmol),[4-(trifluoromethoxy)phenyl]boronic acid (4.48 g, 21.7 mmol) andbis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II)(1.70 g, 2.42 mmol) were dissolved in 1,4-dioxane (100 ml)/water (20 ml)and aqueous (36 ml, 2.0 M, 72 mmol) and was added. The mixture wasstirred for 2 h at 80° C. The reaction was then cooled to rt and dilutedwith EtOAc The organic phase was washed with water, acidified to pH 3using citric acid (10%) and extracted 3x with DCM. The combined organicphase was dried over a silicone filter and concentrated under reducedpressure to give 12.7 g (66% purity, 109% yield) of the title compoundthat was used without further purification.

LC-MS (method 2): Rt=1.18 min; MS (ESIneg): m/z=317 [M−H]⁻

Intermediate 162-(3-fluorophenyl)-6-[4-(trifluoromethoxy)phenyl]pyrimidine-4-carboxylicacid

2-Chloro-6-[4-(trifluoromethoxy)phenyl]pyrimidine-4-carboxylic acid(11.2 g, 66% purity, 23.2 mmol) and (3-fluorophenyl)boronic acid (4.88g, 34.8 mmol) were solubilised in 1,4-dioxane (170 ml) and aqueoussodium carbonate (35 ml, 2.0 M, 70 mmol) was added. The reaction mixturewas sparged with argon and palladiumtetrakis (2.68 g, 2.32 mmol) wasadded. The mixture was stirred for 5 h at 80° C. The mixture wasevaporated and the residue was stirred in HCl (1M) overnight and thesolid was filtered, washed with water and dried under reduced pressureat 60° C. The solid was then stirred in DCM/EtOH overnight, filtered,washed with DCM and dried under reduced pressure to give 3.89 g (98%purity, 43% yield) of the title compound that was used without furtherpurification.

LC-MS (method 2): Rt=1.42 min; MS (ESIneg): m/z=377 [M−H]⁻ ¹H-NMR (400MHz, DMSO-d6): δ [ppm]=7.35-7.42 (m, 1H), 7.55 (d, 2H), 7.61 (td, 1H),8.11 (s, 1H), 8.23-8.29 (m, 1H), 8.36-8.41 (m, 1H), 8.43-8.49 (m, 2H).

EXPERIMENTAL SECTION—EXAMPLES

The following examples describe the embodiment of the instant invention,not restricting the invention to these examples only.

Example 16-(4-Chlorophenyl)-2-(3-fluorophenyl)-N-(2-hydroxy-2-methylpropyl)pyrimidine-4-carboxamide

2-Chloro-6-(4-chlorophenyl)-N-(2-hydroxy-2-methylpropyl)pyrimidine-4-carboxamide(750 mg, 60% purity, 1.32 mmol) and (3-fluorophenyl)boronic acid (278mg, 1.98 mmol) were dissolved in 3.0 mL dioxane, aqueous sodiumcarbonate solution (2.0 mL, 2.0 M, 4.0 mmol) andtetrakis(triphenylphosphine)palladium(0) (153 mg, 132 μmol) were added.The mixture was stirred for 2 h at 90° C. The reaction was diluted withwater and the aqueous mixture was extracted twice with DCM. The organiclayer was dried over a silicone filter and concentrated under reducedpressure. The residue was purified by preparative HPLC to give 71.0 mg(95% purity, 13% yield) of the title compound.

LC-MS (Method 3): Rt=1.46 min; MS (ESIpos): m/z=400 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6): δ [ppm]=1.16 (s, 5H), 3.39 (d, 2H), 4.77 (s,1H), 7.41-7.51 (m, 1H), 7.59-7.70 (m, 3H), 8.42-8.54 (m, 5H), 8.98 (t,1H)

Example 26-(4-Chlorophenyl)-2-(3-fluorophenyl)-N-[(2R)-1-hydroxypropan-2-yl]pyrimidine-4-carboxamide

2-Chloro-6-(4-chlorophenyl)-N-[(2R)-1-hydroxypropan-2-yl]pyrimidine-4-carboxamide(160 mg, 491 μmol) and (3-fluorophenyl)boronic acid (103 mg, 736 μmol)were dissolved in 7.8 mL dioxane, aqueous sodium carbonate solution (740μL, 2.0 M, 1.5 mmol) and tetrakis(triphenylphosphine)palladium(0) (56.7mg, 49.1 μmol) were added. The mixture was stirred for 4 h at 90° C. Themixture was concentrated under reduced pressure. The residue waspurified by preparative HPLC to give 59.0 mg (98% purity, 31% yield) ofthe title compound.

LC-MS (Method 2): Rt=1.42 min; MS (ESIpos): m/z=386 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6): δ [ppm]=1.24 (d, 3H), 3.46-3.62 (m, 2H),4.08-4.20 (m, 1H), 4.89-4.94 (m, 1H), 7.43-7.50 (m, 1H), 7.64-7.70 (m,3H), 8.44-8.49 (m, 3H), 8.51-8.59 (m, 2H), 8.80-8.85 (m, 1H)

Example 32,6-Bis(4-chlorophenyl)-N-[(2S)-1-hydroxypropan-2-yl]pyrimidine-4-carboxamide

2,6-Bis(4-chlorophenyl)pyrimidine-4-carboxylic acid (12.0 mg, 34.8μmol), (2S)-2-aminopropan-1-ol (4.1 μL, 52 μmol), sodium bicarbonate(17.5 mg, 209 μmol) and HATU (39.7 mg, 104 μmol) were stirred in 180 μLDMF overnight at rt. The reaction was diluted with water and the aqueousmixture was extracted with DCM for three times. The organic layer wasdried over a silicone filter and concentrated under reduced pressure.The residue was purified by preparative TLC (EtOAc) to give 10.1 mg (91%purity, 66% yield) of the title compound.

LC-MS (Method 1): Rt=1.53 min; MS (ESIpos): m/z=402 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6): δ [ppm]=1.24 (d, 3H), 3.46-3.61 (m, 2H),4.08-4.19 (m, 1H), 4.93 (t, 1H), 7.67 (d, 4H), 8.41-8.47 (m, 3H), 8.72(d, 2H), 8.75-8.80 (m, 1H)

Example 46-(4-Chlorophenyl)-2-(3-fluorophenyl)-N-[(2S)-1-hydroxypropan-2-yl]pyrimidine-4-carboxamide

2-Chloro-6-(4-chlorophenyl)-N-[(2S)-1-hydroxypropan-2-yl]pyrimidine-4-carboxamide(32.3 mg, 99.0 μmol) and (3-fluorophenyl)boronic acid (20.8 mg, 149μmol) were dissolved in 1.6 mL dioxane, aqueous sodium carbonatesolution (150 μL, 2.0 M, 300 μmol) andtetrakis(triphenylphosphine)palladium(0) (11.4 mg, 9.90 μmol) wereadded. The mixture was stirred for 4 h at 90° C. The mixture wasconcentrated under reduced pressure. The residue was purified by flashchromatography. Received product was precipitated in DMSO, filtered offand dried under reduced pressure to give 11.0 mg (95% purity, 27% yield)of the title compound.

LC-MS (Method 2): Rt=1.42 min; MS (ESIpos): m/z=386 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6): δ [ppm]=1.24 (d, 3H), 3.46-3.61 (m, 2H),4.08-4.20 (m, 1H), 4.89-4.93 (m, 1H), 7.43-7.50 (m, 1H), 7.63-7.71 (m,3H), 8.44-8.58 (m, 5H), 8.79-8.85 (m, 1H)

Example 52-(3-Fluorophenyl)-N-[(2S)-1-hydroxypropan-2-yl]-6-[4-(trifluoromethoxy)phenyl]pyrimidine-4-carboxamide

2-Chloro-N-[(2S)-1-hydroxypropan-2-yl]-6-[4-(trifluoromethoxy)phenyl]pyrimidine-4-carboxamide(19.6 mg, 52.2 μmol) and (3-fluorophenyl)boronic acid (10.9 mg, 78.2μmol) were dissolved in 830 μL dioxane, aqueous sodium carbonatesolution (78 μL, 2.0 M, 160 μmol) andtetrakis(triphenylphosphine)palladium(0) (6.03 mg, 5.22 μmol) wereadded. The mixture was stirred for 4 h at 90° C. The mixture wasconcentrated under reduced pressure. The residue was purified by flashchromatography to give 3.00 mg (95% purity, 13% yield) of the titlecompound.

LC-MS (Method 2): Rt=1.46 min; MS (ESIpos): m/z=436 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6): δ [ppm]=1.25 (d, 3H), 3.46-3.62 (m, 2H),4.08-4.21 (m, 1H), 4.92 (t, 1H), 7.43-7.51 (m, 1H), 7.57-7.62 (m, 2H),7.63-7.70 (m, 1H), 8.48 (s, 1H), 8.51-8.61 (m, 4H), 8.83 (d, 1H)

Example 62-(3-Fluorophenyl)-N-[(2R)-1-hydroxypropan-2-yl]-6-[4-(trifluoromethoxy)phenyl]pyrimidine-4-carboxamide

2-Chloro-N-[(2R)-1-hydroxypropan-2-yl]-6-[4-(trifluoromethoxy)phenyl]pyrimidine-4-carboxamide(150 mg, 399 μmol) and (3-fluorophenyl)boronic acid (83.8 mg, 599 μmol)were dissolved in 6.4 mL dioxane, aqueous sodium carbonate solution (600μL, 2.0 M, 1.2 mmol) and tetrakis(triphenylphosphine)palladium(0) (46.1mg, 39.9 μmol) were added. The mixture was stirred for 4 h at 90° C. Themixture was concentrated under reduced pressure. The residue waspurified by preparative HPLC to give 93.7 mg (95% purity, 51% yield) ofthe title compound.

LC-MS (Method 2): Rt=1.45 min; MS (ESIpos): m/z=436 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6): δ [ppm]=1.25 (d, 3H), 3.47-3.62 (m, 2H),4.08-4.21 (m, 1H), 4.85-4.98 (m, 1H), 7.44-7.51 (m, 1H), 7.57-7.62 (m,2H), 7.63-7.70 (m, 1H), 8.48 (s, 1H), 8.51-8.60 (m, 4H), 8.80-8.86 (m,1H)

Example 72-(3-Fluorophenyl)-N-(2-hydroxy-2-methylpropyl)-6-[4-(trifluoromethoxy)phenyl]pyrimidine-4-carboxamide

2-Chloro-N-(2-hydroxy-2-methylpropyl)-6-[4-(trifluoromethoxy)phenyl]pyrimidine-4-carboxamide(650 mg, 80% purity, 1.33 mmol) and (3-fluorophenyl)boronic acid (280mg, 2.00 mmol) were dissolved in 5.0 mL dioxane, aqueous sodiumcarbonate solution (2.0 mL, 2.0 M, 4.0 mmol) andtetrakis(triphenylphosphine)palladium(0) (154 mg, 133 μmol) were added.The mixture was stirred for 2 h at 90° C. The reaction was diluted withwater and the aqueous mixture was extracted twice with DCM. The organiclayer was dried over a silicone filter and concentrated under reducedpressure. The residue was purified by preparative HPLC to give 121 mg(95% purity, 19% yield) of the title compound.

LC-MS (Method 3): Rt=1.49 min; MS (ESIpos): m/z=450 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6): δ [ppm]=1.17 (s, 6H), 3.39 (d, 2H), 4.77 (s,1H), 7.42-7.50 (m, 1H), 7.58 (d, 2H), 7.66 (td, 1H), 8.44-8.49 (m, 2H),8.51 (dt, 1H), 8.54-8.59 (m, 2H), 8.99 (t, 1H)

Example 82-(3-Fluorophenyl)-N-(2-hydroxy-2-methylpropyl)-6-[4-(trifluoromethyl)phenyl]pyrimidine-4-carboxamide

2-Chloro-N-(2-hydroxy-2-methylpropyl)-6-[4-(trifluoromethyl)phenyl]pyrimidine-4-carboxamide(240 mg, 642 μmol) and (3-fluorophenyl)boronic acid (135 mg, 963 μmol)were dissolved in 2.0 mL dioxane, aqueous sodium carbonate solution (960μL, 2.0 M, 1.9 mmol) and tetrakis(triphenylphosphine)palladium(0) (74.2mg, 64.2 μmol) were added. The mixture was stirred for 2 h at 90° C. Thereaction was diluted with water and the aqueous mixture was extractedtwice with DCM. The organic layer was dried over a silicone filter andconcentrated under reduced pressure. The residue was purified bypreparative HPLC to give 58.0 mg (95% purity, 20% yield) of the titlecompound.

LC-MS (Method 1): Rt=1.49 min; MS (ESIpos): m/z=434 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6): δ [ppm]=1.17 (s, 6H), 4.78 (br s, 1H),7.43-7.52 (m, 1H), 7.68 (td, 1H), 7.97 (d, 2H), 8.47-8.56 (m, 3H), 8.65(d, 2H), 9.03 (t, 1H).

Example 96-(3-Fluorophenyl)-N-[(2S)-1-hydroxypropan-2-yl]-2-[4-(trifluoromethyl)phenyl]pyrimidine-4-carboxamide

2-Chloro-6-(3-fluorophenyl)-N-[(2S)-1-hydroxypropan-2-yl]pyrimidine-4-carboxamide(196 mg, 80% purity, 506 μmol) and [4-(trifluoromethyl)phenyl]boronicacid (144 mg, 759 μmol) were dissolved in a mixture of 7.8 mL dioxaneand 1.6 mL water, aqueous potassium carbonate solution (760 μL, 2.0 M,1.5 mmol) and Xphos precat G1 (41.9 mg, 50.6 μmol) were added. Themixture was stirred for 2 h at 80° C. The reaction was concentratedunder reduced pressure. The residue was purified by preparative HPLC togive 31.0 mg (95% purity, 14% yield of the title compound.

LC-MS (Method 3): Rt=1.40 min; MS (ESIpos): m/z=420 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6): δ [ppm]=1.25 (d, 3H), 3.44-3.62 (m, 2H),4.09-4.20 (m, 1H), 4.92 (t, 1H), 7.45-7.52 (m, 1H), 7.67 (td, 1H), 7.97(d, 2H), 8.25-8.30 (m, 2H), 8.52 (s, 1H), 8.81 (d, 1H), 8.92 (d, 2H)

Example 102-(4-Chlorophenyl)-6-(3-fluorophenyl)-N-[(2S)-1-hydroxypropan-2-yl]pyrimidine-4-carboxamide

2-Chloro-6-(3-fluorophenyl)-N-[(2S)-1-hydroxypropan-2-yl]pyrimidine-4-carboxamide(196 mg, 80% purity, 506 μmol) and (4-chlorophenyl)boronic acid (119 mg,759 μmol) were dissolved in a mixture of 7.8 mL dioxane and 1.6 mLwater, aqueous potassium carbonate solution (760 μL, 2.0 M, 1.5 mmol)and Xphos precat G1 (41.9 mg, 50.6 μmol) were added. The mixture wasstirred for 2 h at 80° C. The reaction was concentrated under reducedpressure. The residue was purified by preparative HPLC to give 20.0 mg(90% purity, 9% yield) of the title compound.

LC-MS (Method 3): Rt=1.38 min; MS (ESIpos): m/z=384 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6): δ [ppm]=1.24 (d, 3H), 3.45-3.61 (m, 2H),4.10-4.19 (m, 1H), 4.91 (t, 1H), 7.44-7.51 (m, 1H), 7.62-7.70 (m, 3H),8.23-8.28 (m, 2H), 8.46 (s, 1H), 8.73-8.77 (m, 2H), 8.78 (d, 1H)

Example 116-(3-Fluorophenyl)-N-[(2S)-1-hydroxypropan-2-yl]-2-[4-(trifluoromethoxy)phenyl]pyrimidine-4-carboxamide

2-Chloro-6-(3-fluorophenyl)-N-[(2S)-1-hydroxypropan-2-yl]pyrimidine-4-carboxamide(196 mg, 80% purity, 506 μmol) and [4-(trifluoromethoxy)phenyl]boronicacid (156 mg, 759 μmol) were dissolved in a mixture of 7.8 mL dioxaneand 1.6 mL water, aqueous potassium carbonate solution (760 μL, 2.0 M,1.5 mmol) and Xphos precat G1 (41.9 mg, 50.6 μmol) were added. Themixture was stirred for 2 h at 80° C. The reaction was concentratedunder reduced pressure. The residue was purified by preparative HPLC togive 28.0 mg (95% purity, 12% yield) of the title compound.

LC-MS (Method 3): Rt=1.42 min; MS (ESIpos): m/z=436 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6): δ [ppm]=1.24 (d, 3H), 3.47-3.61 (m, 2H),4.09-4.19 (m, 1H), 4.92 (t, 1H), 7.44-7.51 (m, 1H), 7.59 (dd, 2H), 7.66(td, 1H), 8.22-8.29 (m, 2H), 8.47 (s, 1H), 8.78 (d, 1H), 8.81-8.86 (m,2H)

Example 12N-[(2S)-1-hydroxypropan-2-yl]-2,6-bis[4-(trifluoromethoxy)phenyl]pyrimidine-4-carboxamide

2,6-Bis[4-(trifluoromethoxy)phenyl]pyrimidine-4-carboxylic acid (9.00mg, 20.3 μmol), (2S)-2-aminopropan-1-ol (2.4 μL, 30 μmol), sodiumbicarbonate (10.2 mg, 122 μmol) and HATU (23.1 mg, 60.8 μmol) werestirred in 110 μL DMF overnight at rt. The reaction was diluted withwater and the aqueous mixture was extracted with DCM for three times.The organic layer was dried over a silicone filter and concentratedunder reduced pressure. The residue was purified by preparative TLC(EtOAc) to give 8.10 mg (90% purity, 72% yield) of the title compound.

LC-MS (Method 1): Rt=1.58 min; MS (ESIpos): m/z=502 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6): δ [ppm]=1.24 (d, 3H), 3.46-3.62 (m, 2H),4.07-4.19 (m, 1H), 4.87-5.01 (m, 1H), 7.59 (d, 4H), 8.56 (d, 2H),8.77-8.86 (m, 3H) (NH proton is not visible)

Example 132-(4-fluorophenyl)-N-(2-hydroxy-2-methylpropyl)-6-[4-(trifluoromethoxy)phenyl]pyrimidine-4-carboxamide

To (4-fluorophenyl)boronic acid (42.0 mg, 300 μmol) a solution of2-chloro-N-(2-hydroxy-2-methylpropyl)-6-[4-(trifluoromethoxy)phenyl]pyrimidine-4-carboxamide(intermediate 5, 58.5 mg, 150 μmol) in 1 mL of dioxane, sodium carbonatein 0.225 mL water and Tetrakis(triphenylphosphin)palladium(0) (34.7 mg,30.0 μmol) in 1 mL of dioxane were added. The reaction was heated 12 hto 90° C. The crude mixture was filtered through a pad of Celite andpurified by preparative HPLC to give the title compound 4.49 mg (98%purity, 7% yield).

LC-MS (method 2): Rt=1.49 min; MS (ESIpos): m/z=450 [M+H]⁺

The following examples were prepared in analogy to example 13:

Structure IUPAC-Name LC-MS (method): Retention time; Mass found Example¹H-NMR Example 14

2-(4-chlorophenyl)-N-(2-hydroxy-2-methylpropyl)-6-[4-(trifluoromethoxy)phenyl]pyrimidine-4-carboxamide LC-MS (method 2):R_(t) = 1.56 min; MS (ESIpos): m/z = 466 [M + H]⁺ Example 15

N-(2-hydroxy-2-methylpropyl)-2-(4-methoxyphenyl)-6-[4-(trifluoromethoxy)phenyl]pyrimidine-4-carboxamide LC-MS (method 2):R_(t) = 1.46 min; MS (ESIpos): m/z = 462 [M + H]⁺ Example 16

N-(2-hydroxy-2-methylpropyl)-2-(3-methylphenyl)-6-[4-(trifluoromethoxy)phenyl]pyrimidine-4-carboxamide LC-MS (method 2):R_(t) = 1.53 min; MS (ESIpos): m/z = 446 [M + H]⁺ Example 17

2-(4-fluoro-3-methylphenyl)-N-(2-hydroxy-2-methylpropyl)-6-[4-(trifluoromethoxy)phenyl] pyrimidine-4-carboxamideLC-MS (method 2): R_(t) = 1.55 min; MS (ESIpos): m/z = 464 [M + H]⁺Example 18

2-(3,5-dichlorophenyl)-N-(2-hydroxy-2-methylpropyl)-6-[4-(trifluoromethoxy)phenyl]pyrimidine-4-carboxamide LC-MS (method 2):R_(t) = 1.66 min; MS (ESIpos): m/z = 500 [M + H]⁺ Example 19

2-[3-chloro-4-(trifluoromethyl)phenyl]-N-(2-hydroxy-2-methylpropyl)-6-[4-(trifluoromethoxy)phenyl]pyrimidine- 4-carboxamideLC-MS (method 2): R_(t) = 1.63 min; MS (ESIpos): m/z = 534 [M + H]⁺Example 20

2-(3-cyanophenyl)-N-(2-hydroxy-2-methylpropyl)-6-[4-(trifluoromethoxy)phenyl]pyrimidine-4-carboxamide LC-MS (method 2):R_(t) = 1.41 min; MS (ESIpos): m/z = 457 [M + H]⁺ Example 21

2-(3-chlorophenyl)-N-(2-hydroxy-2-methylpropyl)-6-[4-(trifluoromethoxy)phenyl]pyrimidine-4-carboxamide LC-MS (method 2):R_(t) = 1.56 min; MS (ESIpos): m/z = 466 [M + H]⁺ Example 22

2-(3,4-dichlorophenyl)-N-(2-hydroxy-2-methylpropyl)-6-[4-(trifluoromethoxy)phenyl]pyrimidine-4-carboxamide LC-MS (method 2):R_(t) = 1.64 min; MS (ESIpos): m/z = 500 [M + H]⁺ Example 23

N-(2-hydroxy-2-methylpropyl)-2,6-bis[4-(trifluoromethoxy)phenyl]pyrimidine-4-carboxamide LC-MS (method 2):R_(t) = 1.59 min; MS (ESIpos): m/z = 516 [M + H]⁺ Example 24

2-(3,5-difluorophenyl)-N-(2-hydroxy-2-methylpropyl)-6-[4-(trifluoromethoxy)phenyl]pyrimidine-4-carboxamide LC-MS (method 2):R_(t) = 1.52 min; MS (ESIpos): m/z = 468 [M + H]⁺ Example 25

2-[4-(difluoromethyl)phenyl]-N-(2-hydroxy-2-methylpropyl)-6-[4-(trifluoromethoxy)phenyl] pyrimidine-4-carboxamideLC-MS (method 2): R_(t) = 1.47 min; MS (ESIpos): m/z = 482 [M + H]⁺Example 26

2-(3-cyano-5-fluorophenyl)-N-(2-hydroxy-2-methylpropyl)-6-[4-(trifluoromethoxy)phenyl] pyrimidine-4-carboxamideLC-MS (method 2): R_(t) = 1.45 min; MS (ESIpos): m/z = 475 [M + H]⁺Example 27

2-(4-bromophenyl)-N-[(2S)-1-hydroxypropan-2-yl]-6-[4-(trifluoromethoxy)phenyl]pyrimidine-4-carboxamide LC-MS (method 2):R_(t) = 1.55 min; MS (ESIpos): m/z = 498 [M + H]⁺ Example 28

2-(4-fluorophenyl)-N-[(2S)-1-hydroxypropan-2-yl]-6-[4-(trifluoromethoxy)phenyl]pyrimidine-4-carboxamide LC-MS (method 2):R_(t) = 1.46 min; MS (ESIpos): m/z = 436 [M + H]⁺ Example 29

2-(4-chlorophenyl)-N-[(2S)-1-hydroxypropan-2-yl]-6-[4-(trifluoromethoxy)phenyl]pyrimidine-4-carboxamide LC-MS (method 2):R_(t) = 1.54 min; MS (ESIpos): m/z = 452 [M + H]⁺ Example 30

N-[(2S)-1-hydroxypropan-2-yl]-2-(4-methoxyphenyl)-6-[4-(trifluoromethoxy)phenyl]pyrimidine-4-carboxamide LC-MS (method 2):R_(t) = 1.43 min; MS (ESIpos): m/z = 448 [M + H]⁺ Example 31

N-[(2S)-1-hydroxypropan-2-yl]-2-(3-methylphenyl)-6-[4-(trifluoromethoxy)phenyl]pyrimidine-4-carboxamide LC-MS (method 2):R_(t) = 1.50 min; MS (ESIpos): m/z = 432 [M + H]⁺ Example 32

2-(4-fluoro-3-methylphenyl)-N-[(2S)-1-hydroxypropan-2-yl]-6-[4-(trifluoromethoxy)phenyl]pyrimidine-4- carboxamide LC-MS(method 2): R_(t) = 1.52 min; MS (ESIpos): m/z = 450 [M + H]⁺ Example 33

2-(3-chloro-4-fluorophenyl)-N-[(2S)-1-hydroxypropan-2-yl]-6-[4-(trifluoromethoxy)phenyl]pyrimidine-4- carboxamide LC-MS(method 2): R_(t) = 1.54 min; MS (ESIpos): m/z = 470 [M + H]⁺ Example 34

2-(3,5-dichlorophenyl)-N-[(2S)-1-hydroxypropan-2-yl]-6-[4-(trifluoromethoxy)phenyl]pyrimidine-4-carboxamide LC-MS (method 2):R_(t) = 1.63 min; MS (ESIpos): m/z = 486 [M + H]⁺ Example 35

2-(3-cyano-4-fluorophenyl)-N-[(2S)-1-hydroxypropan-2-yl]-6-[4-(trifluoromethoxy)phenyl]pyrimidine-4- carboxamide LC-MS(method 2): R_(t) = 1.41 min; MS (ESIpos): m/z = 461 [M + H]⁺ Example 36

2-(3-cyanophenyl)-N-[(2S)-1-hydroxypropan-2-yl]-6-[4-(trifluoromethoxy)phenyl]pyrimidine-4-carboxamide LC-MS (method 2):R_(t) = 1.38 min; MS (ESIpos): m/z = 443 [M + H]⁺ Example 37

2-(3-chlorophenyl)-N-[(2S)-1-hydroxypropan-2-yl]-6-[4-(trifluoromethoxy)phenyl]pyrimidine-4-carboxamide LC-MS (method 2):R_(t) = 1.52 min; MS (ESIpos): m/z = 452 [M + H]⁺ Example 38

2-(3,4-dichlorophenyl)-N-[(2S)-1-hydroxypropan-2-yl]-6-[4-(trifluoromethoxy)phenyl]pyrimidine-4-carboxamide LC-MS (method 2):R_(t) = 1.61 min; MS (ESIpos): m/z = 486 [M + H]⁺ Example 39

2-(3,5-difluorophenyl)-N-[(2S)-1-hydroxypropan-2-yl]-6-[4-(trifluoromethoxy)phenyl]pyrimidine-4-carboxamide LC-MS (method 2):R_(t) = 1.49 min; MS (ESIpos): m/z = 454 [M + H]⁺ Example 40

2-(3-fluoro-5-methoxyphenyl)-N-[(2S)-1-hydroxypropan-2-yl]-6-[4-(trifluoromethoxy)phenyl]pyrimidine-4- carboxamide LC-MS(method 2): R_(t) = 1.47 min; MS (ESIpos): m/z = 466 [M + H]⁺ Example 41

2-(3-fluoro-5-methylphenyl)-N-[(2S)-1-hydroxypropan-2-yl]-6-[4-(trifluoromethoxy)phenyl]pyrimidine-4- carboxamide LC-MS(method 2): R_(t) = 1.52 min; MS (ESIpos): m/z = 450 [M + H]⁺ Example 42

2-[4-(difluoromethyl)phenyl]-N-[(2S)-1-hydroxypropan-2-yl]-6-[4-(trifluoromethoxy)phenyl]pyrimidine-4- carboxamide LC-MS(method 2): R_(t) = 1.44 min; MS (ESIpos): m/z = 468 [M + H]⁺ Example 43

2-(3-cyano-5-fluorophenyl)-N-[(2S)-1-hydroxypropan-2-yl]-6-[4-(trifluoromethoxy)phenyl]pyrimidine-4- carboxamide LC-MS(method 2): R_(t) = 1.42 min; MS (ESIpos): m/z = 461 [M + H]⁺ Example 44

2-(4-bromophenyl)-6-(4-chlorophenyl)-N-(2-hydroxy-2-methylpropyl)pyrimidine-4-carboxamide LC-MS (method 2): R_(t) = 1.60min; MS (ESIpos): m/z = 462 [M + H]⁺ Example 45

6-(4-chlorophenyl)-2-(4-fluorophenyl)-N-(2-hydroxy-2-methylpropyl)pyrimidine-4-carboxamide LC-MS (method 2): R_(t) = 1.43min; MS (ESIpos): m/z = 400 [M + H]⁺ Example 46

2,6-bis(4-chlorophenyl)-N-(2-hydroxy-2-methylpropyl)pyrimidine-4-carboxamide LC-MS (method 2): R_(t) = 1.51 min; MS(ESIpos): m/z = 416 [M + H]⁺ Example 47

6-(4-chlorophenyl)-N-(2-hydroxy-2-methylpropyl)-2-(4-methoxyphenyl)pyrimidine-4-carboxamide LC-MS (method 2): R_(t) = 1.40min; MS (ESIpos): m/z = 412 [M + H]⁺ Example 48

6-(4-chlorophenyl)-N-(2-hydroxy-2-methylpropyl)-2-(3-methylphenyl)pyrimidine-4-carboxamide LC-MS (method 2): R_(t) = 1.48min; MS (ESIpos): m/z = 396 [M + H]⁺ Example 49

6-(4-chlorophenyl)-2-(4-fluoro-3-methylphenyl)-N-(2-hydroxy-2-methylpropyl)pyrimidine-4-carboxamide LC-MS (method 2): R_(t)= 1.50 min; MS (ESIpos): m/z = 414 [M + H]⁺ Example 50

2-(3-chloro-4-fluorophenyl)-6-(4-chlorophenyl)-N-(2-hydroxy-2-methylpropyl)pyrimidine-4-carboxamide LC-MS (method 2): R_(t)= 1.52 min; MS (ESIpos): m/z = 434 [M + H]⁺ Example 51

6-(4-chlorophenyl)-2-(3,5-dichlorophenyl)-N-(2-hydroxy-2-methylpropyl)pyrimidine-4-carboxamide LC-MS (method 2): R_(t) = 1.62min; MS (ESIpos): m/z = 452 [M + H]⁺ Example 52

6-(4-chlorophenyl)-2-(3-cyano-4-fluorophenyl)-N-(2-hydroxy-2-methylpropyl)pyrimidine-4-carboxamide LC-MS (method 2): R_(t)= 1.37 min; MS (ESIpos): m/z = 425 [M + H]⁺ Example 53

6-(4-chlorophenyl)-2-[3-chloro-4-(trifluoromethyl)phenyl]-N-(2-hydroxy-2-methylpropyl)pyrimidine-4- carboxamide LC-MS(method 2): R_(t) = 1.59 min; MS (ESIpos): m/z = 484 [M + H]⁺ Example 54

2-(3-chlorophenyl)-6-(4-chlorophenyl)-N-(2-hydroxy-2-methylpropyl)pyrimidine-4-carboxamide LC-MS (method 2): R_(t) = 1.51min; MS (ESIpos): m/z = 416 [M + H]⁺ Example 55

6-(4-chlorophenyl)-2-(3,4-dichlorophenyl)-N-(2-hydroxy-2-methylpropyl)pyrimidine-4-carboxamide LC-MS (method 2): R_(t) = 1.59min; MS (ESIpos): m/z = 452 [M + H]⁺ Example 56

6-(4-chlorophenyl)-N-(2-hydroxy-2-methylpropyl)-2-[4-(trifluoromethoxy)phenyl]pyrimidine-4-carboxamide LC-MS (method 2):R_(t) = 1.54 min; MS (ESIpos): m/z = 466 [M + H]⁺ Example 57

6-(4-chlorophenyl)-2-(3,5-difluorophenyl)-N-(2-hydroxy-2-methylpropyl)pyrimidine-4-carboxamide LC-MS (method 2): R_(t) = 1.47min; MS (ESIpos): m/z = 418 [M + H]⁺ Example 58

6-(4-chlorophenyl)-2-[3-fluoro-5-(trifluoromethyl)phenyl]-N-(2-hydroxy-2-methylpropyl)pyrimidine-4- carboxamide LC-MS(method 2): R_(t) = 1.54 min; MS (ESIpos): m/z = 468 [M + H]⁺ Example 59

6-(4-chlorophenyl)-2-(3-fluoro-5-methoxyphenyl)-N-(2-hydroxy-2-methylpropyl)pyrimidine-4-carboxamide LC-MS (method 2): R_(t)= 1.45 min; MS (ESIpos): m/z = 430 [M + H]⁺ Example 60

6-(4-chlorophenyl)-2-(3-fluoro-5-methylphenyl)-N-(2-hydroxy-2-methylpropyl)pyrimidine-4-carboxamide LC-MS (method 2): R_(t)= 1.50 min; MS (ESIpos): m/z = 414 [M + H]⁺ Example 61

6-(4-chlorophenyl)-2-[4-(difluoromethyl)phenyl]-N-(2-hydroxy-2-methylpropyl)pyrimidine-4-carboxamide LC-MS (method 2): R_(t)= 1.41 min; MS (ESIpos): m/z = 432 [M + H]⁺ Example 62

6-(4-chlorophenyl)-2-(3-cyano-5-fluorophenyl)-N-(2-hydroxy-2-methylpropyl)pyrimidine-4-carboxamide LC-MS (method 2): R_(t)= 1.39 min; MS (ESIpos): m/z = 425 [M + H]⁺ Example 63

6-(4-chlorophenyl)-N-[(2S)-1-hydroxypropan-2-yl]-2-(4-methoxyphenyl)pyrimidine-4-carboxamide LC-MS (method 2): R_(t) = 1.36min; MS (ESIpos): m/z = 398 [M + H]⁺ Example 64

6-(4-chlorophenyl)-N-[(2S)-1-hydroxypropan-2-yl]-2-(3-methylphenyl)pyrimidine-4-carboxamide LC-MS (method 2): R_(t) = 1.44min; MS (ESIpos): m/z = 382 [M + H]⁺ Example 65

6-(4-chlorophenyl)-2-(4-fluoro-3-methylphenyl)-N-[(2S)-1-hydroxypropan-2-yl]pyrimidine-4-carboxamide LC-MS (method 2):R_(t) = 1.46 min; MS (ESIpos): m/z = 400 [M + H]⁺ Example 66

2-(3-chloro-4-fluorophenyl)-6-(4-chlorophenyl)-N-[(2S)-1-hydroxypropan-2-yl]pyrimidine-4-carboxamide LC-MS (method 2): R_(t) =1.49 min; MS (ESIpos): m/z = 420 [M + H]⁺ Example 67

6-(4-chlorophenyl)-2-(3,5-dichlorophenyl)-N-[(2S)-1-hydroxypropan-2-yl]pyrimidine-4-carboxamide LC-MS (method 2): R_(t) =1.59 min; MS (ESIpos): m/z = 438 [M + H]⁺ Example 68

6-(4-chlorophenyl)-2-(3-cyano-4-fluorophenyl)-N-[(2S)-1-hydroxypropan-2-yl]pyrimidine-4-carboxamide LC-MS (method 2): R_(t) =1.34 min; MS (ESIpos): m/z = 411 [M + H]⁺ Example 69

6-(4-chlorophenyl)-2-[3-chloro-4-(trifluoromethyl)phenyl]-N-[(2S)-1-hydroxypropan-2-yl]pyrimidine-4- carboxamide LC-MS(method 2): R_(t) = 1.56 min; (ESIpos): m/z = 470 [M + H]⁺ Example 70

6-(4-chlorophenyl)-2-(3-cyanophenyl)-N-[(2S)-1-hydroxypropan-2-yl]pyrimidine-4-carboxamide LC-MS (method 2): R_(t) =1.30 min; MS (ESIpos): m/z = 393 [M + H]⁺ Example 71

2-(3-chlorophenyl)-6-(4-chlorophenyl)-N-[(2S)-1-hydroxypropan-2-yl]pyrimidine-4-carboxamide LC-MS (method 2): R_(t) =1.47 min; MS (ESIpos): m/z = 402 [M + H]⁺ Example 72

6-(4-chlorophenyl)-2-(3,4-dichlorophenyl)-N-[(2S)-1-hydroxypropan-2-yl]pyrimidine-4-carboxamide LC-MS (method 2): R_(t) =1.56 min; MS (ESIpos): m/z = 438 [M + H]⁺ Example 73

6-(4-chlorophenyl)-N-[(2S)-1-hydroxypropan-2-yl]-2-[4-(trifluoromethoxy)phenyl]pyrimidine-4-carboxamide LC-MS (method 2):R_(t) = 1.51 min; MS (ESIpos): m/z = 452 [M + H]⁺ Example 74

6-(4-chlorophenyl)-2-(3,5-difluorophenyl)-N-[(2S)-1-hydroxypropan-2-yl]pyrimidine-4-carboxamide LC-MS (method 2): R_(t) =1.43 min; MS (ESIpos): m/z = 404 [M + H]⁺ Example 75

6-(4-chlorophenyl)-2-[3-fluoro-5-(trifluoromethyl)phenyl]-N-[(2S)-1-hydroxypropan-2-yl]pyrimidine-4- carboxamide LC-MS(method 2): R_(t) = 1.51 min; MS (ESIpos): m/z = 454 [M + H]⁺ Example 76

6-(4-chlorophenyl)-2-(3-fluoro-5-methoxyphenyl)-N-[(2S)-1-hydroxypropan-2-yl]pyrimidine-4-carboxamide LC-MS (method 2):R_(t) = 1.41 min; MS (ESIpos): m/z = 416 [M + H]⁺ Example 77

6-(4-chlorophenyl)-2-(3-fluoro-5-methylphenyl)-N-[(2S)-1-hydroxypropan-2-yl]pyrimidine-4-carboxamide LC-MS (method 2): R_(t) =1.46 min; MS (ESIpos): m/z = 400 [M + H]⁺

Example 782-(3-fluorophenyl)-N-[(2S)-1-hydroxy-3-methylbutan-2-yl]-6-[4-(trifluoromethoxy)phenyl]pyrimidine-4-carboxamide

To (2S)-2-amino-3-methylbutan-1-ol (30.9 mg, 300 μmol) a solution of2-(3-fluorophenyl)-6-[4-(trifluoromethoxy)phenyl]pyrimidine-4-carboxylicacid (56.7 mg, 150 μmol) in 1 mL DMF, HATU (171 mg, 450 μmol) in 1 mLDMF and sodium bicarbonate (75.6 mg, 900 μmol) were added. The reactionwas shaked for 3 days at rt. The crude mixture was filtered through apad of Celite and purified by preparative HPLC to give the titlecompound 8.53 mg (100% purity, 12% yield)

LC-MS (method 2): Rt=1.51 min; MS (ESIpos): m/z=464 [M+H]⁺

The following examples were prepared in analogy to example 78:

Structure IUPAC-Name LC-MS (method): Retention time; Mass found Example¹H-NMR Example 79

N-(3,4-dihydroxybutan-2-yl)-2-(3-fluorophenyl)-6-[4-(trifluoromethoxy)phenyl]pyrimidine-4-carboxamide LC-MS (method 2):R_(t) = 1.36 min; MS (ESIpos): m/z = 466 [M + H]⁺ Example 80

N-(3,3-difluoro-2-hydroxycyclohexyl)-2-(3-fluorophenyl)-6-[4-(trifluoromethoxy)phenyl]pyrimidine-4-carboxamide LC-MS (method 2):R_(t) = 1.47 min; MS (ESIpos): m/z = 512 [M + H]⁺ Example 81

2-(3-fluorophenyl)-N-[(1-hydroxycyclohexyl)methyl]-6-[4-(trifluoromethoxy)phenyl]pyrimidine-4-carboxamide LC-MS (method 2):R_(t) = 1.57 min; MS (ESIpos): m/z = 490 [M + H]⁺ Example 82

2-(3-fluorophenyl)-N-[(2S)-1-hydroxy- 3,3-dimethylbutan-2-yl]-6-[4-(trifluoromethoxy)phenyl]pyrimidine-4-carboxamide LC-MS (method 2):R_(t) = 1.55 min; MS (ESIpos): m/z = 478 [M + H]⁺ Example 83

2-(3-fluorophenyl)-N-(1,1,1-trifluoro-4-hydroxybutan-2-yl)-6-[4-(trifluoromethoxy)phenyl]pyrimidine-4-carboxamide LC-MS (method 2):R_(t) = 1.49 min; MS (ESIpos): m/z = 504 [M + H]⁺ Example 84

2-(3-fluorophenyl)-N-[(1S,2S)-2-hydroxycyclohexyl]-6-[4-(trifluoromethoxy)phenyl]pyrimidine-4-carboxamide LC-MS (method 2):R_(t) = 1.50 min; MS (ESIpos): m/z = 476 [M + H]⁺ Example 85

N-(1-cyclobutyl-2-hydroxyethyl)-2-(3-fluorophenyl)-6-[4-(trifluoromethoxy)phenyl]pyrimidine-4-carboxamide LC-MS (method 2):R_(t) = 1.53 min; MS (ESIpos): m/z = 476 [M + H]⁺ Example 86

2-(3-fluorophenyl)-N-[(2R)-1,1,1-trifluoro-3-hydroxy-3-methylbutan-2-yl]-6-[4-(trifluoromethoxy)phenyl]pyrimidine-4-carboxamide LC-MS (method 2):R_(t) = 1.55 min; MS (ESIpos): m/z = 518 [M + H]⁺ Example 87

2-(3-fluorophenyl)-N-[(2R)-1,1,1-trifluoro- 3-hydroxypropan-2-yl]-6-[4-(trifluoromethoxy)phenyl]pyrimidine-4-carboxamide LC-MS (method 2):R_(t) = 1.48 min; MS (ESIpos): m/z = 490 [M + H]⁺ Example 88

2-(3-fluorophenyl)-N-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-6-[4-(trifluoromethoxy)phenyl]pyrimidine-4-carboxamide LC-MS (method 2):R_(t) = 1.48 min; MS (ESIpos): m/z = 490 [M + H]⁺ Example 89

2-(3-fluorophenyl)-N-[(2S)-3-hydroxy-3-methylbutan-2-yl]-6-[4-(trifluoromethoxy)phenyl]pyrimidine-4-carboxamide LC-MS (method 2):R_(t) = 1.50 min; MS (ESIpos): m/z = 464 [M + H]⁺ Example 90

2-(3-fluorophenyl)-N-[(3S,4S)-4-hydroxyoxolan-3-yl]-6-[4-(trifluoromethoxy)phenyl]pyrimidine-4-carboxamide LC-MS (method 2):R_(t) = 1.38 min; MS (ESIpos): m/z = 464 [M + H]⁺ Example 91

2-(3-fluorophenyl)-N-(1,1,1-trifluoro-3-hydroxybutan-2-yl)-6-[4-(trifluoromethoxy)phenyl]pyrimidine-4-carboxamide LC-MS (method 2):R_(t) = 1.51 min; MS (ESIpos): m/z = 504 [M + H]⁺ Example 92

2-(3-fluorophenyl)-N-[(1S,2R)-2-hydroxycyclobutyl]-6-[4-(trifluoromethoxy)phenyl]pyrimidine-4-carboxamide LC-MS (method 2):R_(t) = 1.45 min; MS (ESIpos): m/z = 448 [M + H]⁺ Example 93

2-(3-fluorophenyl)-N-[(1R,2R)-2-hydroxycyclobutyl]-6-[4-(trifluoromethoxy)phenyl]pyrimidine-4-carboxamide LC-MS (method 2):R_(t) = 1.43 min; MS (ESIpos): m/z = 448 [M + H]⁺

EXPERIMENTAL SECTION—BIOLOGICAL ASSAYS

Examples were tested in selected biological assays one or more times.When tested more than once, data are reported as either average valuesor as median values, wherein

-   -   the average value, also referred to as the arithmetic mean        value, represents the sum of the values obtained divided by the        number of times tested, and    -   the median value represents the middle number of the group of        values when ranked in ascending or descending order. If the        number of values in the data set is odd, the median is the        middle value. If the number of values in the data set is even,        the median is the arithmetic mean of the two middle values.

Examples were synthesized one or more times. When synthesized more thanonce, data from biological assays represent average values or medianvalues calculated utilizing data sets obtained from testing of one ormore synthetic batch.

The in vitro activity of the compounds of the present invention can bedemonstrated in the following assays:

Transactivation Assay in Human Cell Line (In Vitro Assay 1)

Transactivation assay was carried out in U87 glioblastoma cells (ATCC)endogenously expressing AHR. In addition the cells were stablytransfected with an AHR inducible firefly luciferase reporter geneconstruct that carried AHR-binding sites (DRE) in its promoter and arenilla reporter gene construct with constitutively active promoter.Kynurenic acid is an endogenous AHR activating ligand and was used toprestimulate test cells prior to testing the antagonistic properties ofcompounds.

In Vitro Assay 1: Antagonism in Human Cell Line

Cells in medium (tryptophan free RPMI (PAN-Biotech # P04-17598), 1% FCS(Biochrome Superior # S0615), 1×Penicillin/Streptomycin (Sigma P0781)supplemented with 150 μM kynurenic acid were grown for 20 hours inabsence (negative control) or presence of increasing concentrations oftest compounds (typical dilutions: 72 μmol/L, 0.25 nmol/L, 0.89 nmol/L;3.1 nmol/L, 11 nmol/L, 38 nmol/L, 130 nmol/L, 470 nmol/L, 1.6 μmol/L,5.7 μmol/L and 20 μmol/L in duplicates). As positive inhibition controlcells supplemented with 150 μM kynurenic acid were incubated in presenceof 5 μM Staurosporin. Normalization was done by positive and negativecontrols.

Firefly luciferase and Renilla activity was determined by the DualGloLuciferase Assay System (Promega, #2920). Renilla activity was used toassess toxic effects of compounds.

Transactivation Assay in Mouse Cell Line (In Vitro Assay 2)

Transactivation assay was carried out in Hepa 1c1c7 cells (ATCC #CRL-2026) endogenously expressing AHR. In addition the cells were stablytransfected with an AHR inducible firefly luciferase reporter geneconstruct that carried AHR-binding sites (DRE) in its promoter.Kynurenic acid is an endogenous AHR activating ligand and was used toprestimulate test cells prior to testing the antagonistic properties ofcompounds.

In Vitro Assay 2: Antagonism in Mouse Cell Line

Cells in medium (tryptophan free RPMI (PAN-Biotech # P04-17598), 1% FCS(Biochrome Superior # S0615), 1×Penicillin/Streptomycin (Sigma P0781)supplemented with 200 μM kynurenic acid (Sigma # K3375) were grown for20 hours in absence (negative control) or presence of increasingconcentrations of test compounds (typical dilutions: 72 μmol/L, 0.25nmol/L, 0.89 nmol/L; 3.1 nmol/L, 11 nmol/L, 38 nmol/L, 130 nmol/L, 470nmol/L, 1.6 μmol/L, 5.7 μmol/L and 20 μmol/L in duplicates). As positiveinhibition control cells without addition of kynurenic acid wereincubated. Normalization was done by positive and negative controls.Firefly luciferase activity was determined by the SteadyGlo LuciferaseAssay System (Promega, # E2550).

TABLE 2 IC₅₀ values of examples in in vitro assays 1 and 2 Example Assay1: Human AhR Assay 2: Mouse AhR No Antagonism IC₅₀ [M] Antagonism IC₅₀[M] 1 >2.00E−05  2 5.88E−09 1.33E−08 3 6.40E−07 5.32E−07 4 1.69E−093.38E−09 5 1.27E−09 1.28E−09 6 1.22E−08 1.78E−08 7 >2.00E−05  >2.00E−05 8 >2.00E−05  >2.00E−05  9 1.53E−08 8.64E−09 10 3.53E−08 2.38E−08 114.11E−08 1.15E−08 12 >2.00E−05  >2.00E−5  1.79E−5  13 2.60E−08 142.34E−07 1.48E−07 15 3.90E−07 >2.00E−5  16 1.29E−08 17 6.37E−07 18 19 201.14E−08 1.25E−07 21 22 2.78E−07 23 24 2.83E−08 25 >2.00E−5  26 4.02E−0827 28 2.20E−07 1.08E−07 29 5.25E−07 6.97E−07 30 7.30E−07 31 2.64E−084.69E−08 32 1.67E−07 3.84E−07 33 9.84E−08 3.97E−07 34 1.70E−07 357.83E−08 36 1.84E−08 1.80E−07 37 8.49E−09 38 4.35E−06 39 1.23E−08 40 412.95E−08 1.91E−07 42 1.10E−06 1.10E−06 43 2.15E−08 44 >2.00E−5  452.44E−08 1.61E−07 46 9.79E−06 47 2.22E−06 48 2.60E−08 49 4.06E−07 505.38E−08 51 1.01E−07 3.09E−06 52 1.12E−07 53 54 55 56 57 58 7.76E−08 5960 9.08E−07 61 >2.00E−5  7.12E−06 62 5.78E−08 63 3.92E−07 5.15E−06 647.20E−09 5.26E−08 65 4.85E−08 1.34E−07 66 2.35E−08 1.48E−07 67 1.01E−0768 1.02E−07 69 70 1.93E−08 2.15E−07 71 1.36E−08 72 3.61E−07 73 9.72E−0674 1.70E−08 75 9.78E−08 76 3.68E−08 8.15E−08 77 2.64E−08 79 5.30E−092.37E−09 80 6.43E−09 6.91E−09 78 81 82 83 84 85 1.28E−08 86 87 88 89 9091 >2.00E−5  >2.00E−5  92 93

1: A compound of formula (I):

wherein X is CH or N; Y is CR³ or N; Z is CH or N, wherein if X is N, Yis CR³ and Z is CH, and if X is CH, Z is CH and Y is CR³ or N, and if Zis N, Y is N and X is CH; R¹ is C₂-C₈-hydroxyalkyl, wherein saidC₂-C₈-hydroxyalkyl groups are optionally substituted once with R⁷ andoptionally one to three times with halogen, or C₃-C₆-cycloalkylsubstituted once with hydroxy or C₁-C₃-hydroxyalkyl and optionally oneto three times with halogen, or (C₃-C₆-cycloalkyl substituted once withhydroxy)-C₁-C₄-alkyl, or 5- to 6-membered heterocycloalkyl optionallysubstituted once with hydroxy or C₁-C₃-hydroxyalkyl and optionally oneto three times with halogen, or (5- to 6-membered heterocycloalkyloptionally substituted once with hydroxy)-C₁-C₄-alkyl; R² is hydrogen,chloro, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, methoxy,difluoromethoxy, trifluoromethoxy, or —NR⁸R⁹; R³ is hydrogen, halogen,or methyl; R⁴ is hydrogen, methyl, fluoromethyl, difluoromethyl,trifluoromethyl, methoxy, halogen, or cyano; R⁵ is hydrogen, halogen,methyl, fluoromethyl, difluoromethyl, trifluoromethyl, methoxy,difluoromethoxy, or trifluoromethoxy; R⁶ is hydrogen or halogen; R⁷ isC₁-C₄-alkoxy, —CO₂—R¹⁰, —CO—NR⁸R⁹, cyano, —NR⁸R⁹, C₃-C₆-cycloalkyl, 5-to 6-membered heterocycloalkyl, phenyl, or monocyclic heteroaryl; R⁸ andR⁹ are the same or different and are, independently from each other,hydrogen or C₁-C₃-alkyl, or together with the nitrogen atom to whichthey are attached form a 4- to 6-membered nitrogen containingheterocyclic ring, said ring optionally containing one additionalheteroatom selected from the group consisting of O, S, NH, and NR^(a) inwhich R^(a) is a C₁-C₄-alkyl group; and R¹⁰ is hydrogen or C₁-C₄-alkyl;or a polymorph, an enantiomer, a diastereomer, a racemate, a tautomer,an N-oxide, a hydrate, or a solvate, a physiologically acceptable salt,a solvate of a physiologically acceptable salt thereof, or a mixture ofany of the foregoing. 2: The compound according to claim 1, wherein: Xis CH; Y is CR³; Z s CH; R¹ is C₂-C₆-hydroxyalkyl, wherein saidC₂-C₆-hydroxyalkyl groups are optionally substituted once withcyclobutyl and optionally one to three times with fluoro, orC₄-C₆-cycloalkyl substituted once with hydroxy and optionally one to twotimes with fluoro, or (C₄-C₆-cycloalkyl substituted once withhydroxy)-methyl, or 4-hydroxyoxolan-3-yl; R² is hydrogen, chloro,trifluoromethyl, or trifluoromethoxy; R³ is hydrogen or fluoro; R⁴ ishydrogen, fluoro, chloro, cyano, methyl, trifluoromethyl, or methoxy; R⁵is hydrogen, fluoro, chloro, bromo, difluoromethyl, trifluoromethyl,methoxy, or trifluoromethoxy; R⁶ is hydrogen, fluoro, or chloro; or apolymorph, an enantiomer, a diastereomer, a racemate, a tautomer, anN-oxide, a hydrate, or a solvate, a physiologically acceptable salt, asolvate of a physiologically acceptable salt thereof, or a mixture ofany of the foregoing. 3: The compound according to claim 1 which isselected from the group consisting of6-(4-chlorophenyl)-2-(3-fluorophenyl)-N-(2-hydroxy-2-methylpropyl)pyrimidine-4-carboxamide;6-(4-chlorophenyl)-2-(3-fluorophenyl)-N-[(2R)-1-hydroxypropan-2-yl]pyrimidine-4-carboxamide;2,6-bis(4-chlorophenyl)-N-[(2S)-1-hydroxypropan-2-yl]pyrimidine-4-carboxamide;6-(4-chlorophenyl)-2-(3-fluorophenyl)-N-[(2S)-1-hydroxypropan-2-yl]pyrimidine-4-carboxamide;2-(3-fluorophenyl)-N-[(2S)-1-hydroxypropan-2-yl]-6-[4-(trifluoromethoxy)phenyl]pyrimidine-4-carboxamide;2-(3-fluorophenyl)-N-[(2R)-1-hydroxypropan-2-yl]-6-[4-(trifluoromethoxy)phenyl]pyrimidine-4-carboxamide;2-(3-fluorophenyl)-N-(2-hydroxy-2-methylpropyl)-6-[4-(trifluoromethoxy)phenyl]pyrimidine-4-carboxamide;2-(3-fluorophenyl)-N-(2-hydroxy-2-methylpropyl)-6-[4-(trifluoromethyl)phenyl]pyrimidine-4-carboxamide;6-(3-fluorophenyl)-N-[(2S)-1-hydroxypropan-2-yl]-2-[4-(trifluoromethyl)phenyl]pyrimidine-4-carboxamide;2-(4-chlorophenyl)-6-(3-fluorophenyl)-N-[(2S)-1-hydroxypropan-2-yl]pyrimidine-4-carboxamide;6-(3-fluorophenyl)-N-[(2S)-1-hydroxypropan-2-yl]-2-[4-(trifluoromethoxy)phenyl]pyrimidine-4-carboxamide;N-[(2S)-1-hydroxypropan-2-yl]-2,6-bis[4-(trifluoromethoxy)phenyl]pyrimidine-4-carboxamide;2-(4-fluorophenyl)-N-(2-hydroxy-2-methylpropyl)-6-[4-(trifluoromethoxy)phenyl]pyrimidine-4-carboxamide;2-(4-chlorophenyl)-N-(2-hydroxy-2-methylpropyl)-6-[4-(trifluoromethoxy)phenyl]pyrimidine-4-carboxamide;N-(2-hydroxy-2-methylpropyl)-2-(4-methoxyphenyl)-6-[4-(trifluoromethoxy)phenyl]pyrimidine-4-carboxamide;N-(2-hydroxy-2-methylpropyl)-2-(3-methylphenyl)-6-[4-(trifluoromethoxy)phenyl]pyrimidine-4-carboxamide;2-(4-fluoro-3-methylphenyl)-N-(2-hydroxy-2-methylpropyl)-6-[4-(trifluoromethoxy)phenyl]pyrimidine-4-carboxamide;2-(3,5-dichlorophenyl)-N-(2-hydroxy-2-methylpropyl)-6-[4-(trifluoromethoxy)phenyl]pyrimidine-4-carboxamide;2-[3-chloro-4-(trifluoromethyl)phenyl]-N-(2-hydroxy-2-methylpropyl)-6-[4-(trifluoromethoxy)phenyl]pyrimidine-4-carboxamide;2-(3-cyanophenyl)-N-(2-hydroxy-2-methylpropyl)-6-[4-(trifluoromethoxy)phenyl]pyrimidine-4-carboxamide;2-(3-chlorophenyl)-N-(2-hydroxy-2-methylpropyl)-6-[4-(trifluoromethoxy)phenyl]pyrimidine-4-carboxamide;2-(3,4-dichlorophenyl)-N-(2-hydroxy-2-methylpropyl)-6-[4-(trifluoromethoxy)phenyl]pyrimidine-4-carboxamide;N-(2-hydroxy-2-methylpropyl)-2,6-bis[4-(trifluoromethoxy)phenyl]pyrimidine-4-carboxamide;2-(3,5-difluorophenyl)-N-(2-hydroxy-2-methylpropyl)-6-[4-(trifluoromethoxy)phenyl]pyrimidine-4-carboxamide;2-[4-(difluoromethyl)phenyl]-N-(2-hydroxy-2-methylpropyl)-6-[4-(trifluoromethoxy)phenyl]pyrimidine-4-carboxamide;2-(3-cyano-5-fluorophenyl)-N-(2-hydroxy-2-methylpropyl)-6-[4-(trifluoromethoxy)phenyl]pyrimidine-4-carboxamide;2-(4-bromophenyl)-N-[(2S)-1-hydroxypropan-2-yl]-6-[4-(trifluoromethoxy)phenyl]pyrimidine-4-carboxamide;2-(4-fluorophenyl)-N-[(2S)-1-hydroxypropan-2-yl]-6-[4-(trifluoromethoxy)phenyl]pyrimidine-4-carboxamide;2-(4-chlorophenyl)-N-[(2S)-1-hydroxypropan-2-yl]-6-[4-(trifluoromethoxy)phenyl]pyrimidine-4-carboxamide;N-[(2S)-1-hydroxypropan-2-yl]-2-(4-methoxyphenyl)-6-[4-(trifluoromethoxy)phenyl]pyrimidine-4-carboxamide;N-[(2S)-1-hydroxypropan-2-yl]-2-(3-methylphenyl)-6-[4-(trifluoromethoxy)phenyl]pyrimidine-4-carboxamide;2-(4-fluoro-3-methylphenyl)-N-[(2S)-1-hydroxypropan-2-yl]-6-[4-(trifluoromethoxy)phenyl]pyrimidine-4-carboxamide;2-(3-chloro-4-fluorophenyl)-N-[(2S)-1-hydroxypropan-2-yl]-6-[4-(trifluoromethoxy)phenyl]pyrimidine-4-carboxamide;2-(3,5-dichlorophenyl)-N-[(2S)-1-hydroxypropan-2-yl]-6-[4-(trifluoromethoxy)phenyl]pyrimidine-4-carboxamide;2-(3-cyano-4-fluorophenyl)-N-[(2S)-1-hydroxypropan-2-yl]-6-[4-(trifluoromethoxy)phenyl]pyrimidine-4-carboxamide;2-(3-cyanophenyl)-N-[(2S)-1-hydroxypropan-2-yl]-6-[4-(trifluoromethoxy)phenyl]pyrimidine-4-carboxamide;2-(3-chlorophenyl)-N-[(2S)-1-hydroxypropan-2-yl]-6-[4-(trifluoromethoxy)phenyl]pyrimidine-4-carboxamide;2-(3,4-dichlorophenyl)-N-[(2S)-1-hydroxypropan-2-yl]-6-[4-(trifluoromethoxy)phenyl]pyrimidine-4-carboxamide;2-(3,5-difluorophenyl)-N-[(2S)-1-hydroxypropan-2-yl]-6-[4-(trifluoromethoxy)phenyl]pyrimidine-4-carboxamide;2-(3-fluoro-5-methoxyphenyl)-N-[(2S)-1-hydroxypropan-2-yl]-6-[4-(trifluoromethoxy)phenyl]pyrimidine-4-carboxamide;2-(3-fluoro-5-methylphenyl)-N-[(2S)-1-hydroxypropan-2-yl]-6-[4-(trifluoromethoxy)phenyl]pyrimidine-4-carboxamide;2-[4-(difluoromethyl)phenyl]-N-[(2S)-1-hydroxypropan-2-yl]-6-[4-(trifluoromethoxy)phenyl]pyrimidine-4-carboxamide;2-(3-cyano-5-fluorophenyl)-N-[(2S)-1-hydroxypropan-2-yl]-6-[4-(trifluoromethoxy)phenyl]pyrimidine-4-carboxamide;2-(4-bromophenyl)-6-(4-chlorophenyl)-N-(2-hydroxy-2-methylpropyl)pyrimidine-4-carboxamide;6-(4-chlorophenyl)-2-(4-fluorophenyl)-N-(2-hydroxy-2-methylpropyl)pyrimidine-4-carboxamide;2,6-bis(4-chlorophenyl)-N-(2-hydroxy-2-methylpropyl)pyrimidine-4-carboxamide;6-(4-chlorophenyl)-N-(2-hydroxy-2-methylpropyl)-2-(4-methoxyphenyl)pyrimidine-4-carboxamide;6-(4-chlorophenyl)-N-(2-hydroxy-2-methylpropyl)-2-(3-methylphenyl)pyrimidine-4-carboxamide;6-(4-chlorophenyl)-2-(4-fluoro-3-methylphenyl)-N-(2-hydroxy-2-methylpropyl)pyrimidine-4-carboxamide;2-(3-chloro-4-fluorophenyl)-6-(4-chlorophenyl)-N-(2-hydroxy-2-methylpropyl)pyrimidine-4-carboxamide;6-(4-chlorophenyl)-2-(3,5-dichlorophenyl)-N-(2-hydroxy-2-methylpropyl)pyrimidine-4-carboxamide;6-(4-chlorophenyl)-2-(3-cyano-4-fluorophenyl)-N-(2-hydroxy-2-methylpropyl)pyrimidine-4-carboxamide;6-(4-chlorophenyl)-2-[3-chloro-4-(trifluoromethyl)phenyl]-N-(2-hydroxy-2-methylpropyl)pyrimidine-4-carboxamide;2-(3-chlorophenyl)-6-(4-chlorophenyl)-N-(2-hydroxy-2-methylpropyl)pyrimidine-4-carboxamide;6-(4-chlorophenyl)-2-(3,4-dichlorophenyl)-N-(2-hydroxy-2-methylpropyl)pyrimidine-4-carboxamide;6-(4-chlorophenyl)-N-(2-hydroxy-2-methylpropyl)-2-[4-(trifluoromethoxy)phenyl]pyrimidine-4-carboxamide; 6-(4-chlorophenyl)-2-(3,5-difluorophenyl)-N-(2-hydroxy-2-methylpropyl)pyrimidine-4-carboxamide;6-(4-chlorophenyl)-2-[3-fluoro-5-(trifluoromethyl)phenyl]-N-(2-hydroxy-2-methylpropyl)pyrimidine-4-carboxamide;6-(4-chlorophenyl)-2-(3-fluoro-5-methoxyphenyl)-N-(2-hydroxy-2-methylpropyl)pyrimidine-4-carboxamide;6-(4-chlorophenyl)-2-(3-fluoro-5-methylphenyl)-N-(2-hydroxy-2-methylpropyl)pyrimidine-4-carboxamide;6-(4-chlorophenyl)-2-[4-(difluoromethyl)phenyl]-N-(2-hydroxy-2-methylpropyl)pyrimidine-4-carboxamide;6-(4-chlorophenyl)-2-(3-cyano-5-fluorophenyl)-N-(2-hydroxy-2-methylpropyl)pyrimidine-4-carboxamide;6-(4-chlorophenyl)-N-[(2S)-1-hydroxypropan-2-yl]-2-(4-methoxyphenyl)pyrimidine-4-carboxamide;6-(4-chlorophenyl)-N-[(2S)-1-hydroxypropan-2-yl]-2-(3-methylphenyl)pyrimidine-4-carboxamide;6-(4-chlorophenyl)-2-(4-fluoro-3-methylphenyl)-N-[(2S)-1-hydroxypropan-2-yl]pyrimidine-4-carboxamide;2-(3-chloro-4-fluorophenyl)-6-(4-chlorophenyl)-N-[(2S)-1-hydroxypropan-2-yl]pyrimidine-4-carboxamide;6-(4-chlorophenyl)-2-(3,5-dichlorophenyl)-N-[(2S)-1-hydroxypropan-2-yl]pyrimidine-4-carboxamide;6-(4-chlorophenyl)-2-(3-cyano-4-fluorophenyl)-N-[(2S)-1-hydroxypropan-2-yl]pyrimidine-4-carboxamide;6-(4-chlorophenyl)-2-[3-chloro-4-(trifluoromethyl)phenyl]-N-[(2S)-1-hydroxypropan-2-yl]pyrimidine-4-carboxamide;6-(4-chlorophenyl)-2-(3-cyanophenyl)-N-[(2S)-1-hydroxypropan-2-yl]pyrimidine-4-carboxamide;2-(3-chlorophenyl)-6-(4-chlorophenyl)-N-[(2S)-1-hydroxypropan-2-yl]pyrimidine-4-carboxamide;6-(4-chlorophenyl)-2-(3,4-dichlorophenyl)-N-[(2S)-1-hydroxypropan-2-yl]pyrimidine-4-carboxamide;6-(4-chlorophenyl)-N-[(2S)-1-hydroxypropan-2-yl]-2-[4-(trifluoromethoxy)phenyl]pyrimidine-4-carboxamide;6-(4-chlorophenyl)-2-(3,5-difluorophenyl)-N-[(2S)-1-hydroxypropan-2-yl]pyrimidine-4-carboxamide;6-(4-chlorophenyl)-2-[3-fluoro-5-(trifluoromethyl)phenyl]-N-[(2S)-1-hydroxypropan-2-yl]pyrimidine-4-carboxamide;6-(4-chlorophenyl)-2-(3-fluoro-5-methoxyphenyl)-N-[(2S)-1-hydroxypropan-2-yl]pyrimidine-4-carboxamide;6-(4-chlorophenyl)-2-(3-fluoro-5-methylphenyl)-N-[(2S)-1-hydroxypropan-2-yl]pyrimidine-4-carboxamide;2-(3-fluorophenyl)-N-[(2S)-1-hydroxy-3-methylbutan-2-yl]-6-[4-(trifluoromethoxy)phenyl]pyrimidine-4-carboxamide;N-(3,4-dihydroxybutan-2-yl)-2-(3-fluorophenyl)-6-[4-(trifluoromethoxy)phenyl]pyrimidine-4-carboxamide;N-(3,3-difluoro-2-hydroxycyclohexyl)-2-(3-fluorophenyl)-6-[4-(trifluoromethoxy)phenyl]pyrimidine-4-carboxamide;2-(3-fluorophenyl)-N-[(1-hydroxycyclohexyl)methyl]-6-[4-(trifluoromethoxy)phenyl]pyrimidine-4-carboxamide;2-(3-fluorophenyl)-N-[(2S)-1-hydroxy-3,3-dimethylbutan-2-yl]-6-[4-(trifluoromethoxy)phenyl]pyrimidine-4-carboxamide;2-(3-fluorophenyl)-N-(1,1,1-trifluoro-4-hydroxybutan-2-yl)-6-[4-(trifluoromethoxy)phenyl]pyrimidine-4-carboxamide;2-(3-fluorophenyl)-N-[(1 S,2S)-2-hydroxycyclohexyl]-6-[4-(trifluoromethoxy)phenyl]pyrimidine-4-carboxamide;N-(1-cyclobutyl-2-hydroxyethyl)-2-(3-fluorophenyl)-6-[4-(trifluoromethoxy)phenyl]pyrimidine-4-carboxamide;2-(3-fluorophenyl)-N-[(2R)-1,1,1-trifluoro-3-hydroxy-3-methylbutan-2-yl]-6-[4-(trifluoromethoxy)phenyl]pyrimidine-4-carboxamide;2-(3-fluorophenyl)-N-[(2R)-1,1,1-trifluoro-3-hydroxypropan-2-yl]-6-[4-(trifluoromethoxy)phenyl]pyrimidine-4-carboxamide;2-(3-fluorophenyl)-N-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-6-[4-(trifluoromethoxy)phenyl]pyrimidine-4-carboxamide;2-(3-fluorophenyl)-N-[(2S)-3-hydroxy-3-methylbutan-2-yl]-6-[4-(trifluoromethoxy)phenyl]pyrimidine-4-carboxamide;2-(3-fluorophenyl)-N-[(3 S,4S)-4-hydroxyoxolan-3-yl]-6-[4-(trifluoromethoxy)phenyl]pyrimidine-4-carboxamide;2-(3-fluorophenyl)-N-(1,1,1-trifluoro-3-hydroxybutan-2-yl)-6-[4-(trifluoromethoxy)phenyl]pyrimidine-4-carboxamide;2-(3-fluorophenyl)-N-[(1S,2R)-2-hydroxycyclobutyl]-6-[4-(trifluoromethoxy)phenyl]pyrimidine-4-carboxamide;and2-(3-fluorophenyl)-N-[(1R,2R)-2-hydroxycyclobutyl]-6-[4-(trifluoromethoxy)phenyl]pyrimidine-4-carboxamide;or a polymorph, an enantiomer, a diastereomer, a racemate, a tautomer,an N-oxide, a hydrate, or a solvate, a physiologically acceptable salt,a solvate of a physiologically acceptable salt thereof, or a mixture ofany of the foregoing. 4: A method of preparing a compound of formula (I)according to claim 1, said method comprising the step of reacting anintermediate compound of formula (VII):

in which X, Y, Z, R², R⁴, R⁵ and R⁶ are as defined for the compound ofgeneral formula (I) according to claim 1, with a compound of formula(VIII):H₂N—R¹  (III), in which R¹ is as defined for the compound of formula (I)according to claim 1, thereby giving a compound of formula (I):

in which X, Y, Z, R¹, R², R⁴, R⁵ and R⁶ are as defined for the compoundof formula (I) according to claim
 1. 5. (canceled) 6: A pharmaceuticalcomposition comprising a compound of formula (I) according to claim 1,or a polymorph, an enantiomer, a diastereomer, a racemate, a tautomer,an N-oxide, a hydrate, or a solvate, a physiologically acceptable salt,a solvate of a physiologically acceptable salt thereof, or a mixture ofany of the foregoing, and one or more pharmaceutically acceptableexcipients. 7: A pharmaceutical combination comprising: one or morecompounds of formula (I) according to claim 1, or a polymorph, anenantiomer, a diastereomer, a racemate, a tautomer, an N-oxide, ahydrate, or a solvate, a physiologically acceptable salt, a solvate of aphysiologically acceptable salt thereof, or a mixture of any of theforegoing, and one or more pharmaceutically active anti cancer compoundsor one or more pharmaceutically active immune checkpoint inhibitors. 8:A method for treatment or prophylaxis of a disease, comprisingadministering a therapeutically effective amount of a compound offormula (I) according to claim 1, or a polymorph, an enantiomer, adiastereomer, a racemate, a tautomer, an N-oxide, a hydrate, or asolvate, a physiologically acceptable salt, a solvate of aphysiologically acceptable salt thereof, or a mixture of any of theforegoing, to a subject in need thereof.
 9. (canceled) claim 10: Themethod according to claim 8, wherein the disease is a cancer, or acondition with dysregulated immune responses, or a disorder associatedwith aberrant AHR signaling. 11: A compound of formula (VII):

in which X, Y, Z, R², R⁴, R⁵ and R⁶ are as defined for the compound ofgeneral formula (I) according to claim
 1. 12. (canceled) 13: The methodaccording to claim 8, wherein the disease is a liquid tumour or a solidtumour.